Heterocyclic Modulators of Lipid Synthesis

ABSTRACT

Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders.

RELATED APPLICATIONS

This application claims the benefit of the earlier filed U.S.Application No. 61/450,561 filed Mar. 8, 2011; U.S. Application No.61/508,611 filed Jul. 16, 2011 and U.S. Application 61/585,642 filed onJan. 11, 2012 each of which are hereby incorporated by reference intheir entirety for all purposes.

FIELD

The present disclosure relates generally to heterocyclic modulators oflipid synthesis and methods of use thereof. The present heterocyclicmodulators of lipid synthesis can be used for the treatment of disorderscharacterized by disregulation in the fatty acid synthase function in asubject by modulating the fatty acid synthase pathway and/or the fattyacid synthase function.

BACKGROUND

Viral disease is a significant health concern that threatens largesegments of human populations. Some of the features related to viralinfection which are of concern to health care professionals include itshighly contagious nature (e.g., HIV, SARS, etc.) and high mutability.Some viruses are also oncogenic (such as HPV, EBV and HBV). Whileviruses are structurally amongst the simplest of organisms, they areregarded to be among the most difficult to control and present aformidable challenge for antiviral drug R&D.

Thus far, there have been a few antiviral drugs widely used in patients,such as Amantadine and Oseltamivir for influenza, Acyclovir forHSV-related infections, Ganciclovir for CMV infection, and multipleagents including co-formulated drugs (Efavirenz, emtricitabine, andtonfovir disoproxil fumarate) for AIDS treatments. These drugs possess avariety of undesirable neurological, metabolic and immunologicalside-effects. Therefore, development of new antiviral therapy has becomea major focus of medical and pharmaceutical research and development.

Infection by hepatitis C virus (HCV) is a serious health issue. It isestimated that 170 million people worldwide are chronically infectedwith HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liverfailure and hepatocellular carcinoma. Chronic HCV infection is thus amajor worldwide cause of liver-related premature mortality.

The present standard of care treatment regimen for HCV infectioninvolves combination therapy with interferon-alpha and ribavirin, oftenwith the addition of a direct-acting protease inhibitor (Telaprevir orBoceprevir). The treatment is cumbersome and sometimes has debilitatingand severe side effects. For this reason, many patients are not treatedin early stages of the disease. Additionally, some patient populationsdo not durably respond to treatment. New and effective methods oftreating HCV infection are urgently needed.

The dominant therapeutic approaches that are currently employed to treatcancer include surgical removal of primary tumors, tumor irradiation,and parenteral application of anti-mitotic cytotoxic agents.Unfortunately, only a relatively small cross-section of cancer patientshave tumors that are “addicted” to a specific pathway, and can thereforebe treated with newer targeted agents. The continued dominance of theselong established therapies is mirrored by the lack of improvement insurvival rates for most cancers. In addition to limited clinicalsuccess, devastating side effects accompany classic therapies. Bothradiation- and cytotoxic-based therapies result in the destruction ofrapidly dividing hematopoietic and intestinal epithelial cells leadingto compromised immune function, anemia, and impaired nutrientabsorption. Surgical intervention often results in a release of tumorcells into the circulation or lymph systems from which metastatic tumorscan subsequently be established. Improved methods for the treatment ofcancer are needed.

SUMMARY

The present disclosure addresses the deficiencies for antiviral andanticancer treatments by providing novel heterocyclic modulators oflipid synthesis having improved antiviral and anticancer activities.

In various aspects, the present disclosure provides for compounds ofStructure (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructure (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   L and D are each independently C or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₂, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructure (III):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   Q is C or N;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q        is N then R₃ is absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₅, R₆, R₂, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;    -   n is 0, 1, or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructures (IV-A), (IV-B), or (IV-C):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁, L₂, L₃, L₄, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl;    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken        together with the atoms to which they are attached join together        to form a heterocyclyl, heteroaryl, or cycloalkyl;    -   R₂₆ is hydrogen, heteroaryl, heterocycyl, —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofStructure (V):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₇ is N or O, wherein R₃₀ is absent if L₇ is O;    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆),        —C(═O)R₄₆, —R₄₈C(═O)R₄₇, or R₂₉ and R₃₀ taken together with the        atoms to which they are attached join together to form a        heteroaryl or heterocyclyl, wherein R₃₀ is absent if L₇ is O;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino; and    -   v is 0 or 1.

In various aspects, the present disclosure provides for compounds ofStructures (VI-A) or (VI-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁₃, L₁₄, L₁₅, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃,        —OCF₃, —S(═O)R₂₀, or —N(R₁₅R₁₆);    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofStructure (VI-J):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and    -   R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl,        heterocyclyl, aryl or heteroaryl.

In some aspects of Structure (VI-J), R³ is H or halogen.

In some aspects of Structure (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl.

In some aspects of Structure (VI-J), R³ is H or F.

In some aspects of Structure (VI-J), R¹ is —CN.

In some aspects of Structure (VI-J), R¹ is —CF₃.

In some aspects of Structure (VI-J), R²² is H, methyl or ethyl.

In some aspects of Structure (VI-J), R²² is H.

In some aspects of Structure (VI-J), R²² is methyl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—NHR³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is hydrogen, R³is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ whereR³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—O—R³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Structure (VI-J), compounds have a structure selectedfrom the group consisting of:

In various aspects, the present disclosure provides for compounds ofStructures (VII-A) or (VII-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;    -   L₁₇, L₁₈, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl,        C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl,        —N(R₁₃R₁₄), or R₄₁ and R₄₂ taken together with the atoms to        which they are attached join together to form a heteroaryl or        heterocyclyl;    -   R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,        hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N,        or R₄₁ and R₄₂ taken together with the atoms to which they are        attached join together to form a heteroaryl or heterocyclyl;    -   R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In various aspects, the present disclosure provides for compounds ofStructures (VIII-A), (VIII-B), or (VIII-C):

or a pharmaceutically acceptable salt thereof, wherein:

L₁₉ and A are each independently CH or N;

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclyl,        heteroaryl, alkylamino, —S(═O)₂R₂₀, —C(═O)R, or —N(R₁₃R₁₄); and    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In various aspects, compounds of Structure (IX) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)(C₃-C₅ cycloalkyl), or        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:        -   t is 0 or 1;        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Structure (IX), R²⁴ is C₁-C₄ straight or branchedalkyl or —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) whereint is 0 or 1.

In some aspects of Structure (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2;

In some aspects of Structure (IX), R³ is H or halogen.

In some aspects of Structure (IX), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (IX), both L¹ and L² are N.

In some aspects of Structure (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅cycloalkyl and R²² is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (IX), R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl) wherein t is 0 or 1.

In some aspects of Structure (IX), R²¹ is —C₃-C₅ cycloalkyl, R²² isC₁-C₂ alkyl and R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl.

In some aspects of Structure (IX), R³ is H or F.

In some aspects of Structure (IX), R¹ is —CN.

In some aspects of Structure (IX), R¹ is —CF₃.

In some aspects of Structure (IX), R²² is H, methyl or ethyl.

In some aspects of Structure (IX), R²² is H.

In some aspects of Structure (IX), R²² is methyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), compounds have a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (X) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH or halogen;    -   L³ is C(R⁶⁰)₂, O or NR⁵⁰;    -   each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅        cycloalkyl), —O—(C₁-C₄ straight or branched alkyl), or        —C(O)—N(R⁶⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or        branched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic        alkyl optionally containing an oxygen or nitrogen heteroatom,        —C(O)—N(R⁵⁰¹)₂, C₁-C₄ straight or branched alkyl wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   n is 1, 2 or 3;    -   m is 1 or 2;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom    -   R²² is H, halogen, C₁-C₂ alkyl;    -   each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or        branched alkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl),        —C(O)—O_(t)—(C₁-C₄ alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   s is 0, 1 or 2;    -   each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or        branched alkyl; and    -   wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to        form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may        be two R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹.

In some aspects of Structure (X), R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Structure (X), R³ is H or halogen.

In some aspects of Structure (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Structure (X), R³ is H or F.

In some aspects of Structure (X), R¹ is —CN.

In some aspects of Structure (X), R¹ is —CF₃.

In some aspects of Structure (X), n is 1.

In some aspects of Structure (X), n is 2.

In some aspects of Structure (X), m is 1

In some aspects of Structure (X), m is 2.

In some aspects of Structure (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Structure (X), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (X), n is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂alkyl).

In some aspects of Structure (X), L³ is NR⁵⁰; R⁵⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Structure (X), n is 2, m is 1, L³ is O and s is 0.

In some aspects of Structure (X), R²² is H, methyl or ethyl.

In some aspects of Structure (X), R²² is methyl.

In some aspects of Structure (X), R²² is H.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is O.

In some aspects of Structure (X), the compound has a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (XI) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, C₁-C₂ alkyl; and    -   R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In some aspects of Structure (XI), R³ is H or halogen.

In some aspects of Structure (XI), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl.

In some aspects of Structure (XI), R³ is H or F.

In some aspects of Structure (XI), R¹ is —CN.

In some aspects of Structure (XI), R¹ is —CF₃.

In some aspects of Structure (XI), R²² is H, methyl or ethyl.

In some aspects of Structure (XI), R²² is H.

In some aspects of Structure (XI), R²² is methyl.

In some aspects of Structure (XI), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Structure (XI), the compound has a structure selectedfrom the group consisting of:

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In various aspects, the present disclosure provides methods of treatinga condition characterized by disregulation of a fatty acid synthasefunction in subject, the method comprising administering to the subjectin need of such treatment an effective amount of a compound of any oneof the Structures (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X) or (XI). In various aspects the condition characterized bydisregulation of the fatty acid synthase function is a viral infectionor cancer. In various aspects the viral infection is treated using acompound of any one of the Structures (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X) or (XI) in combination with one or moreadditional antiviral treatments. In various aspects the cancer istreated using a compound of any one of the Structures (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination withone or more additional cancer treatments. In various aspects, the viralinfection is hepatitis C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a correlation between FASN inhibition and HCVinhibition.

DETAILED DESCRIPTION

The present disclosure addresses the deficiencies in treating conditionscharacterized by disregulation of the FASN function in a subject, suchas viral infection, cancer and metabolic disorders, by providing novelheterocyclic modulators of lipid synthesis.

In certain aspects, the present disclosure provides compositions andmethods for treatment of viral infections. In general, the compositionsand methods for treatment of viral infections are directed towardmodulation of the fatty acid synthesis pathway. The fatty acid synthesispathway is involved in the replication of viruses into the host cells.The present invention embodies methods for the treatment of viralinfection, such as hepatitis C infections, yellow fever infections, andhuman rhinovirus infections, or any virus that targets the fatty acidsynthesis pathway.

In certain aspects, the present disclosure provides compositions andmethods for the treatment of cancer. Fatty acid synthase is responsiblefor conversion of malonyl-CoA into long-chain fatty acids, which is anearly reaction in fatty acid biosynthesis. Fatty acid synthase isoverexpressed in many cancer cells. Without being bound by anyparticular theory, it is hypothesized that inhibition of fatty acidsynthase expression or fatty acid synthase activity selectivitysuppresses proliferation and induces cell death of cancer cells, withlittle toxicity towards normal cells.

Further, the present disclosure provides compounds and methods formodulating host cell targets that are targeted by viruses. Suchmodulation of host cell targets can include either activation orinhibition of the host cell targets. Accordingly, compounds thatmodulate, e.g., inhibit, the activity of a non-viral protein, e.g., ahost cell protein, e.g., components of the fatty acid synthesis pathway,can be used as antiviral pharmaceutical agents.

DEFINITIONS

Chemical moieties referred to as univalent chemical moieties (e.g.,alkyl, aryl, etc.) also encompass structurally permissible multivalentmoieties, as understood by those skilled in the art. For example, whilean “alkyl” moiety generally refers to a monovalent radical (e.g.,CH₃CH₂—), in appropriate circumstances an “alkyl” moiety can also referto a divalent radical (e.g., —CH₂CH₂—, which is equivalent to an“alkylene” group). Similarly, under circumstances where a divalentmoiety is required, those skilled in the art will understand that theterm “aryl” refers to the corresponding divalent arylene group.

All atoms are understood to have their normal number of valences forbond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the atom's oxidation state). On occasion a moiety can bedefined, for example, as (A)_(a)B, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

Where a substituent can vary in the number of atoms or groups of thesame kind (e.g., alkyl groups can be C₁, C₂, C₃, etc.), the number ofrepeated atoms or groups can be represented by a range (e.g., C₁-C₆alkyl) which includes each and every number in the range and any and allsub ranges. For example, C₁-C₃ alkyl includes C₁, C₂, C₃, C₁₂, C₁₋₃, andC₂₋₃ alkyl.

“Alkanoyl” refers to a carbonyl group with a lower alkyl group as asubstituent.

“Alkylamino” refers to an amino group substituted by an alkyl group.

“Alkoxy” refers to an O-atom substituted by an alkyl group as definedherein, for example, methoxy [—OCH₃, a C₁alkoxy]. The term “C₁₋₆ alkoxy”encompasses C₁ alkoxy, C₂ alkoxy, C₃ alkoxy, C₄ alkoxy, C₅ alkoxy, C₆alkoxy, and any sub-range thereof.

“Alkoxycarbonyl” refers to a carbonyl group with an alkoxy group as asubstituent.

“Alkyl,” “alkenyl,” and “alkynyl,” refer to optionally substituted,straight and branched chain aliphatic groups having from 1 to 30 carbonatoms, or preferably from 1 to 15 carbon atoms, or more preferably from1 to 6 carbon atoms. Examples of alkyl groups include, withoutlimitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, andpropynyl. The term “heteroalkyl” as used herein contemplates an alkylwith one or more heteroatoms.

“Alkylene” refers to an optionally substituted divalent radical which isa branched or unbranched hydrocarbon fragment containing the specifiednumber of carbon atoms, and having two points of attachment. An exampleis propylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Amino” refers to the group —NH₂.

“Aryl” refers to optionally substituted aromatic groups which have atleast one ring having a conjugated pi electron system and includescarbocyclic aryl, and biaryl groups, all of which can be optionallysubstituted. Phenyl and naphthyl groups are preferred carbocyclic arylgroups.

“Aralkyl” or “arylalkyl” refer to alkyl-substituted aryl groups.Examples of aralkyl groups include butylphenyl, propylphenyl,ethylphenyl, methylphenyl, 3,5-dimethylphenyl, tert-butylphenyl.

“Carbamoyl” as used herein contemplates a group of the structure

where in R^(N) is selected from the group consisting of hydrogen, —OH,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

“Carbonyl” refers to a group of the structure

“Cycloalkyl” refers to an optionally substituted ring, which can besaturated or unsaturated and monocyclic, bicyclic, or tricyclic formedentirely from carbon atoms. An example of a cycloalkyl group is thecyclopentenyl group (C₅H₇—), which is a five carbon (C₅) unsaturatedcycloalkyl group.

“Heterocycle” refers to an optionally substituted 5- to 7-memberedcycloalkyl ring system containing 1, 2 or 3 heteroatoms, which can bethe same or different, selected from N, O or S, and optionallycontaining one double bond.

“Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. Theterm “halogen” also contemplates terms “halo” or “halide.”

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present disclosure.

“Heteroaryl” refers to optionally substituted aryl groups having from 1to 9 carbon atoms and the remainder of the atoms are heteroatoms, andincludes those heterocyclic systems described in “Handbook of Chemistryand Physics,” 49th edition, 1968, R. C. Weast, editor; The ChemicalRubber Co., Cleveland, Ohio. See particularly Section C, Rules forNaming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitableheteroaryls include thienyl, pyrryl, furyl, pyridyl, pyrimidyl,pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl,pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl,benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl,benzothiadiazolyl, and the like.

An “optionally substituted” moiety can be substituted with from one tofour, or preferably from one to three, or more preferably one or twonon-hydrogen substituents. Unless otherwise specified, when thesubstituent is on a carbon, it is selected from the group consisting of—OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, none of which are further substituted. Unlessotherwise specified, when the substituent is on a nitrogen, it isselected from the group consisting of C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamidenone of which are further substituted.

The term “sulfonamide” as used herein contemplates a group having thestructure

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R⁵ is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkanoyl, or C₁-C₁₀alkoxycarbonyl.

“Sulfonyl” as used herein alone or as part of another group, refers toan SO₂ group. The SO₂ moiety is optionally substituted.

Compounds of the present disclosure can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present disclosure contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of the present disclosure. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present disclosure can be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Also, moieties disclosed herein which exist in multiple tautomeric formsinclude all such forms encompassed by a given tautomeric structure.

Individual atoms in the disclosed compounds may be any isotope of thatelement. For example hydrogen may be in the form of deuterium.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans. It can be material which isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include, forexample, acid addition salts and base addition salts.

“Acid addition salts” according to the present disclosure, are formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

“Base addition salts” according to the present disclosure are formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. Acceptable inorganicbases include aluminum hydroxide, calcium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydroxide, and the like. It shouldbe understood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature can cause asingle crystal form to dominate.

The term “treating” includes the administration of the compounds oragents of the present invention to a subject to prevent or delay, toalleviate, or to arrest or inhibit development of the symptoms orconditions associated with fatty acid synthase-associated disorders,e.g., tumor growth associated with cancer. A skilled medicalpractitioner will know how to use standard methods to determine whethera patient is suffering from a disease associated with activity of fattyacid synthase, e.g., by examining the patient and determining whetherthe patient is suffering from a disease known to be associated withfatty acid synthase activity or by assaying for fatty acid synthaselevels in blood plasma or tissue of the individual suspected ofsuffering from fatty acid synthase associated disease and comparingfatty acid synthase levels in the blood plasma or tissue of theindividual suspected of suffering from a fatty acid synthase associateddisease fatty acid synthase levels in the blood plasma or tissue of ahealthy individual. Increased securin levels are indicative of disease.Accordingly, the present invention provides, inter alia, methods ofadministering a compound of the present invention to a subject anddetermining fatty acid synthase activity in the subject. Fatty acidsynthase activity in the subject can be determined before and/or afteradministration of the compound.

A “therapeutically effective amount” or “pharmaceutically effectiveamount” means the amount that, when administered to a subject, produceseffects for which it is administered. For example, a “therapeuticallyeffective amount,” when administered to a subject to inhibit fatty acidsynthase activity, is sufficient to inhibit fatty acid synthaseactivity. A “therapeutically effective amount,” when administered to asubject for treating a disease, is sufficient to effect treatment forthat disease.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryaspect of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat are associated with the targeted or suspected disease or condition.These and other routine methods allow the clinician to select patientsin need of therapy using the methods and formulations of the presentinvention.

FASN Pathway Modulators

One aspect of the present disclosure includes a method of inhibitingviral infection or treating cancer by contacting a cell with an agentthat modulates the fatty acid synthesis pathway. This method ofinhibiting viral infection or treating cancer can be performed in vitroby contacting virally infected/cancerous cells with an agent thatmodulates the fatty acid synthesis pathway, or in vivo by administeringan agent that modulates the fatty acid synthesis pathway to a subjectinfected with a virus/having cancer. In one aspect, an agent can be aninhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of the fatty acid synthesis pathway that can beused in the methods and compositions of the present disclosure aredescribed below.

Compounds of Structure (I)

In various aspects, the present disclosure provides for compounds ofStructure (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In certain aspects of Structure (I), R₃ is F.

In certain aspects of Structure (I), A is CH.

In certain aspects of Structure (I), A is N.

In certain aspects of Structure (I), X, Y, and Z are NR′.

In certain aspects of Structure (I), R₄ is heteroaryl, heterocyclyl,—C(═O)N(R₅R₆), —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₄and R₁₁ taken together with the atoms to which they are attached jointogether to form a heteroaryl.

In certain aspects of Structure (I), R₅ is hydrogen and R₆ is aryl orheteroaryl.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-A) or (I-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino; and    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-C) or (I-D):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-E), (I-F), (I-G), (I-H):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-I), (I-J), or (I-K):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-L) or (I-M):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-N) or (I-O):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have the followingStructure (I-P):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-Q), (I-R), or (I-S):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have the followingStructure (I-T):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₂, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (I) have the followingStructure (I-U):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-V):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Structure (I) has the followingStructure (I-W):

or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Structure (I) have one of thefollowing Structures (I-X), (I-Y), (I-Z), (I-AA), (I-AB), (I-AC),(I-AD), (I-AF), (I-AG), or (I-AH):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (II)

In various aspects, the present disclosure provides for compounds ofStructure (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   L and D are each independently C or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and Ru taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆);    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In certain aspects, the compounds of Structure (II) have the followingStructure (II-A):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (II) have the followingStructure (II-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (II) have one of thefollowing Structures (II-C), (II-D), or (II-E):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Structure (II) has the followingStructure (II-F):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (III)

In various aspects, the present disclosure provides for compounds ofStructure (III):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   Q is C or N;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q        is NR₃ is absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₂, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆);    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;    -   n is 0, 1, or 2; and    -   m is 0 or 1.

In certain aspects, the compounds of Structure (III) have one of thefollowing Structures (III-A), (III-B), or (III-C):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Structure (III) have one of thefollowing Structures (III-D), (III-E), or (III-F):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (IV)

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-A), (IV-B), or (IV-C):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁, L₂, L₃, L₄, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl;    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken        together with the atoms to which they are attached join together        to form a heterocyclyl, heteroaryl, or cycloalkyl;    -   R₂₆ is hydrogen, heteroaryl, heterocycyl, —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-D) and (IV-E):

or a pharmaceutically acceptable salt thereof.

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₆ is hydrogen, heteroaryl, heterocycyl, —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-F) and (IV-G):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino;    -   s is 0, 1, or 2;    -   L₅ is CH₂, NH, S, or O;    -   L₆ is CH or N;    -   R₂₇ is hydrogen, —C(═O)R″, —S(═O)₂R₂₀;    -   R₂₈ is hydrogen, —C(═O)R″, —S(═O)₂R₂₀, or is absent if L₆ is O;        and    -   R″ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄), or        —N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), R₁ is cyano.

In certain aspects of Structure (IV), R₂ is hydrogen or halo; R₂ ishydrogen.

In certain aspects of Structure (IV), R₃ is hydrogen.

In certain aspects of Structure (IV), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (IV), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (IV), R₂₅ is hydrogen.

In certain aspects of Structure (IV), L₂ is N.

In certain aspects of Structure (IV), L₁ is CH.

In certain aspects of Structure (IV), L₃ is CH.

In certain aspects of Structure (IV), L₄ is CH.

In certain aspects of Structure (IV), A is N.

In certain aspects of Structure (IV), A is CH.

In certain aspects of Structure (IV), R₂₆ is heterocyclyl.

In certain aspects of Structure (IV), R₂₄ is —N(R₁₃)(R₁₄).

In certain aspects of Structure (IV), L₅ and L₆ are each independentlyN. In certain aspects of Structure (IV), s is 1.

In certain aspects of Structure (IV), s is 0.

In certain aspects, the compounds of Structure (IV) have one of thefollowing Structures (IV-H), (IV-I), (IV-J), (IV-K), (IV-L), (IV-M),(IV-N), or (IV-O):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (V)

In various aspects, the present disclosure provides for compounds ofStructure (V):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₇ is N or O, wherein R₃₀ is absent if L₇ is O;    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆),        —C(═O)R₄₆, —R₄₈C(═O)R₄₇, or R₂₉ and R₃₀ taken together with the        atoms to which they are attached join together to form a        heteroaryl or heterocyclyl, wherein R₃₀ is absent if L₇ is O;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino; and    -   v is 0 or 1.

In certain aspects, the compounds of Structure (V) have one of thefollowing Structures (V-A), (V-B), (V-C), or (V-D):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₀ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl,        heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or        —R₄₈C(═O)R₄₇, wherein R₃₀ is absent if L₂ is o;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino;    -   L₈, L₉, and L₁₀ are each independently CH₂, NH, or O;    -   L₁₁ and L₁₂ are each independently CH or N;    -   R₃₂ and R₃₃ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, —S(═O)₂R₂₀, —C(═O)R₄₆, hydroxyalkyl, hydroxyl, or are        absent;    -   u is 0, 1, or 2; and    -   t is 0, 1, or 2.

In certain aspects of Structure (V), L₇ is N.

In certain aspects of Structure (V), L₇ is O.

In certain aspects of Structure (V), A is N.

In certain aspects of Structure (V), A is CH.

In certain aspects of Structure (V), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (V), R₁ is cyano.

In certain aspects of Structure (V), R₂ is hydrogen or halo.

In certain aspects of Structure (V), R₂ is hydrogen.

In certain aspects of Structure (V), R₃ is fluorine.

In certain aspects of Structure (V), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (V), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (V), R₃₁ is hydrogen.

In certain aspects of Structure (V), R₃₀ is hydrogen.

In certain aspects of Structure (V), L₈ is O.

In certain aspects of Structure (V), L₉ is O.

In certain aspects of Structure (V), L₁₀ is O and L₁₁ is N.

In certain aspects of Structure (V), L₁₂ is N.

In certain aspects of Structure (V), R₃₂ and R₃₃ are each independentlyhydrogen.

In certain aspects, the compounds of Structure (V) have one of thefollowing Structures (V-I), (V-J), (V-K), (V-L), (V-M), (V-N), or (V-O):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (VI)

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-A) or (VI-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁₃, L₁₄, L₁₅, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃,        —OCF₃, —S(═O)₂R₂₀, or —N(R₁₅R₁₆);    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₁₀ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₁₀ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-C) or (VI-D):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₁₀ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₁₀ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₁₀        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₁₀ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₁₀ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino; and    -   R₃₇ and R₃₈ are each independently hydrogen, C₁₋₁₀ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, or R₃₇ and R₃₈        taken together with the atoms to which they are attached join        together to form a heteroaryl or heterocyclyl.

In certain aspects of Structure (VI), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₁₀ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (VI), R₁ is cyano.

In certain aspects of Structure (VI), R₂ is hydrogen or halo.

In certain aspects of Structure (VI), R₂ is hydrogen.

In certain aspects of Structure (VI), R₃ is fluorine.

In certain aspects of Structure (VI), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VI), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Structure (VI), R₃₅ is hydrogen.

In certain aspects of Structure (VI), R₃₄ is heteroaryl;

In certain aspects of Structure (VI), R₃₄ is thienyl, pyrryl, furyl,pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl,pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,thiadiazolyl, benzothiazolyl, or benzothiadiazolyl.

In certain aspects of Structure (VI), L₁₃ is N.

In certain aspects of Structure (VI), L₁₄ and L₁₅ are each independentlyCH.

In certain aspects of Structure (VI), A is N.

In certain aspects of Structure (VI), A is CH.

In certain aspects, the compounds of Structure (VI) have one of thefollowing Structures (VI-E), (VI-F), (VI-G), (VI-H), or (VI-I):

or a pharmaceutically acceptable salt thereof.

In various aspects, the present disclosure provides for compounds ofStructure (VI-J):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and    -   R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl,        heterocyclyl, aryl or heteroaryl, each of which is optionally        substituted.

In some aspects of Structure (VI-J), R³ is H or halogen.

In some aspects of Structure (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (VI-J), R²¹ is cyclobutyl.

In some aspects of Structure (VI-J), R³ is H or F.

In some aspects of Structure (VI-J), R¹ is —CN.

In some aspects of Structure (VI-J), R¹ is —CF₃.

In some aspects of Structure (VI-J), R²² is H, methyl or ethyl.

In some aspects of Structure (VI-J), R²² is H.

In some aspects of Structure (VI-J), R²² is methyl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—NHR³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵ is —C(O)—O—R³⁵¹.

In some aspects of Structure (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Structure (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Structure (VI-J), compounds have a structure selectedfrom the group consisting of:

Compounds of Structure (VII)

In certain aspects, the compounds of Structure (VII) have one of thefollowing Structures (VII-A) or (VII-B):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;    -   L₁₇, L₁₈, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl,        C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl,        —N(R₁₃R₁₄), or R₄₁ and R₄₂ taken together with the atoms to        which they are attached join together to form a heteroaryl or        heterocyclyl;    -   R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,        hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N,        or R₄₁ and R₄₂ taken together with the atoms to which they are        attached join together to form a heteroaryl or heterocyclyl;    -   R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In certain aspects of Structure (VII), R₁ is hydrogen, cyano, C₁₋₆alkyl, C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Structure (VII), R₁ is cyano.

In certain aspects of Structure (VII), R₂ is hydrogen or halo.

In certain aspects of Structure (VII), R₂ is hydrogen.

In certain aspects of Structure (VII), R₃ is hydrogen.

In certain aspects of Structure (VII), R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₃₉ is hydrogen.

In certain aspects of Structure (VII), R₄₀ is hydrogen.

In certain aspects of Structure (VII), L₁₆ is N.

In certain aspects of Structure (VII), L₁₇ is N.

In certain aspects of Structure (VII), L₁₈ is CH.

In certain aspects of Structure (VII), L₁₈ is N.

In certain aspects of Structure (VII), A is N.

In certain aspects of Structure (VII), A is CH.

In certain aspects of Structure (VII), R₄₂ is C₁₋₆ alkyl.

In certain aspects of Structure (VII), R₄₁ is C₁₋₆ alkyl.

In certain aspects, the compounds of Structure (VII) have one of thefollowing Structures (VII-C) or (VII-D):

or a pharmaceutically acceptable salt thereof.

Compounds of Structure (VIII)

In certain aspects, the compounds of Structure (VIII) have one of thefollowing Structures (VIII-A), (VIII-B), or (VIII-C):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   L₁₉ and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclyl,        heteroaryl, alkylamino, —S(═O)₂R₂₀, —C(═O)R, or —N(R₁₃R₁₄); and    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In certain aspects of Structure (VIII), R₁ is hydrogen, cyano, C₁₋₆alkyl, C₁₋₆ alkoxy, or —C(═O)NN(R₁₃)(R₁₄).

In certain aspects of Structure (VIII), R₁ is cyano.

In certain aspects of Structure (VIII), R₂ is hydrogen or halo.

In certain aspects of Structure (VIII), R₂ is hydrogen.

In certain aspects of Structure (VIII), R₃ is hydrogen.

In certain aspects of Structure (VIII), R₂₁ and R₂₂ are eachindependently hydrogen or C₁₋₆ alkyl.

In certain aspects of Structure (VIII), R₂₁ and R₂₂ are eachindependently C₁₋₆ alkyl.

In certain aspects of Structure (VIII), R₃₉ is hydrogen.

In certain aspects of Structure (VIII), L₁₉ is N.

In certain aspects of Structure (VIII), A is N.

In certain aspects of Structure (VIII), A is CH.

In certain aspects, the compounds of Structure (VIII) have the followingStructure (VIII-D):

or a pharmaceutically acceptable salt thereof.

In various aspects, compounds of formula IX are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl) or —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃—O₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:        -   t is 0 or 1;        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Structure (IX), R²⁴ is C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein tis 0 or 1.

In some aspects of Structure (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2;

In some aspects of Structure (IX), R³ is H or halogen.

In some aspects of Structure (IX), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (IX), both L¹ and L² are N.

In some aspects of Structure (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅cycloalkyl and R²² is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (IX), R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl) wherein t is 0 or 1.

In some aspects of Structure (IX), R²¹ is C₃-C₅ cycloalkyl, R²² is C₁-C₂alkyl and

R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Structure (IX), R²¹ is cyclobutyl.

In some aspects of Structure (IX), R³ is H or F.

In some aspects of Structure (IX), R¹ is —CN.

In some aspects of Structure (IX), R¹ is —CF₃.

In some aspects of Structure (IX), R²² is H, methyl or ethyl.

In some aspects of Structure (IX), R²² is H.

In some aspects of Structure (IX), R²² is methyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is hydrogen, R³ isH or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴is methyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Structure (IX), compounds have a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (X) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH or halogen;    -   L³ is C(R⁶⁰)₂, O or NR⁵⁰;    -   each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅        cycloalkyl), —O—(C₁-C₄ straight or branched alkyl), or        —C(O)—N(R⁶⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or        branched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic        alkyl optionally containing an oxygen or nitrogen heteroatom,        —C(O)—N(R⁵⁰¹)₂, C₁-C₄ straight or branched alkyl wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   n is 1, 2 or 3;    -   m is 1 or 2;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom    -   R²² is H, halogen, C₁-C₂ alkyl;    -   each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or        branched alkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl),        —C(O)—O_(t)—(C₁-C₄ alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   s is 0, 1 or 2;    -   each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or        branched alkyl; and    -   wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to        form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may        be two R²⁶, two R⁶⁰, two R⁵⁰¹ or two R⁶⁰¹.

In some aspects of Structure (X), R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Structure (X), R³ is H or halogen.

In some aspects of Structure (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Structure (X), R³ is H or F.

In some aspects of Structure (X), R¹ is —CN.

In some aspects of Structure (X), R¹ is —CF₃.

In some aspects of Structure (X), n is 1.

In some aspects of Structure (X), n is 2.

In some aspects of Structure (X), m is 1

In some aspects of Structure (X), m is 2.

In some aspects of Structure (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Structure (X), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (X), n is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂alkyl).

In some aspects of Structure (X), L³ is NR⁵⁰; R⁵⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Structure (X), n is 2, m is 1, L³ is O and s is 0.

In some aspects of Structure (X), R²² is H, methyl or ethyl.

In some aspects of Structure (X), R²² is methyl.

In some aspects of Structure (X), R²² is H.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Structure (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is 0.

In some aspects of Structure (X), the compound has a structure selectedfrom the group consisting of:

In various aspects, compounds of Structure (XI) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, C₁-C₂ alkyl; and    -   R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In some aspects of Structure (XI), R³ is H or halogen.

In some aspects of Structure (XI), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Structure (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Structure (XI), R²¹ is cyclobutyl.

In some aspects of Structure (XI), R³ is H or F.

In some aspects of Structure (XI), R¹ is —CN.

In some aspects of Structure (XI), R¹ is —CF₃.

In some aspects of Structure (XI), R²² is H, methyl or ethyl.

In some aspects of Structure (XI), R²² is H.

In some aspects of Structure (XI), R²² is methyl.

In some aspects of Structure (XI), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Structure (XI), the compound has a structure selectedfrom the group consisting of:

In certain aspects, the present disclosure provides compounds having anyone of the structures found in Table 1. According to the presentdisclosure, the compounds of Table 1 are inhibitors of fatty acidsynthase.

Synthesis of Compounds

Also described herein are methods of synthesizing the compounds of thepresent disclosure. Compounds of the present disclosure can besynthesized as indicated in SYNTHETIC SCHEMES 1-13 below.

wherein:

-   -   R″ is hydrogen or alkyl;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino; and        -   R₁₇ is hydrogen or alkyl.

wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl; and        -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy,            (C₁₋₆ alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄            taken together with the atoms to which they are attached            join together to form a heterocyclyl, heteroaryl, or            cycloalkyl.

wherein:

-   -   LG is a leaving group;    -   Nu is a nucleophile;    -   L₂, L₃, L₄, and L₄, are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino; and        -   R₁₇ is hydrogen or alkyl.

wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino;        -   R₁₇ is hydrogen or alkyl; and    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), or heterocyclyl.

wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino;    -   R₁₇ is hydrogen or alkyl;    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), or heterocyclyl;    -   R₂₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl,        heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or        —R₄₈C(═O)R₄₇;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃,        —OCF₃, —S(═O)₂R₂₀, or —N(R₁₅R₁₆); and    -   m 0, 1, or 2.

Schemes 6-13 provides a synthesis for exemplary compounds of formula IXwherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²³ is H or C₁-C₄ straight or branched alkyl; and    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)(C₃-C₅ cycloalkyl), or        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:        -   t is 0 or 1; and    -   the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen        heteroatom.

Additional methods for producing particular compounds according to thepresent disclosure are provided in the EXAMPLES. One skilled in the artwill recognize that other compounds of structures can be made bymodifications to the specifically disclosed schemes employing methodsknown to those of skill in the art. Additional examples can be found inTable 1.

Many such techniques are well known in the art. However, many of theknown techniques are elaborated in Compendium of Organic SyntheticMethods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5,1984; and Vol. 6 as well as March in Advanced Organic Chemistry (1985);Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes (1993); Advanced OrganicChemistry Part B: Reactions and Synthesis, Second Edition (1983);Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, SecondEdition (1977); Protecting Groups in Organic Synthesis, Second Edition;and Comprehensive Organic Transformations (1999).

Viral Infection Pathways

The host cell targets inhibited by the present compounds and methodsplay a role in the viral replication and/or infection pathways.Targeting of such host cell targets modulates the replication and/orinfection pathways of the viruses. In preferred aspects the identifiedhost cell targets are directly or indirectly modulated using thecompositions of the present disclosure. The modulation of such host celltargets can also be performed by targeting entities in the upstream ordownstream signaling pathways of the host cell targets.

According to the present disclosure, viral infection can be treated bytargeting the fatty acid synthesis pathway, and in particular fatty acidsynthase. HRV is representative of viruses that can be treated accordingto the present disclosure. Like other viruses, the replication of HRVinvolves six phases; transmission, entry, replication, biosynthesis,assembly, and exit. Entry occurs by endocytosis, replication and vRNPassembly takes place in the nucleus, and the virus buds from the plasmamembrane. In the infected patient, the virus targets airway epithelialcells. The present compounds and methods target and modulate at leastone host cell targets involved in such pathways.

For some viruses a great deal of progress has been made in theelucidation of the steps involved during infection of host cells. Forexample, experiments initiated in the early 1980s showed that influenzavirus follows a stepwise, endocytic entry program with elements sharedwith other viruses such as alpha- and rhabdoviruses (Marsh and Helenius1989; Whittaker 2006). The steps include: 1) Initial attachment tosialic acid containing glycoconjugates receptors on the cell surface; 2)signaling induced by the virus particle; 3) endocytosis byclathrin-dependent and clathrin-independent cellular mechanism; 4)acid-induced, hemaglutinin (HA)-mediated penetration from lateendosomes; 5) acid-activated, M2 and matrix protein (M1) dependentuncoating of the capsid; and, 6) intra-cytosolic transport and nuclearimport of vRNPs. These steps depend on assistance from the host cell inthe form of sorting receptors, vesicle formation machinery,kinase-mediated regulation, organelle acidification, and, most likely,activities of the cytoskeleton.

Influenza attachment to the cells surface occurs via binding of the HA1subunit to cell surface glycoproteins and glycolipids that carryoligosaccharide moieties with terminal sialic acid residues (Skehel andWiley 2000). The linkage by which the sialic acid is connected to thenext saccharide contributes to species specificity. Avian strainsincluding H₅N₁ prefer an a-(2,3)-link and human strains a-(2,6)-link(Matrosovich 2006). In epithelial cells, binding occurs preferentiallyto microvilli on the apical surface, and endocytosis occurs at base ofthese extensions (Matlin 1982). Whether receptor binding induces signalsthat prepare the cell for the invasion is not yet known, but it islikely because activation of protein kinase C and synthesis ofphopshatidylinositol-3-phosphate (PI3P) are required for efficient entry(Sieczkarski et al. 2003; Whittaker 2006).

Endocytic internalization occurs within a few minutes after binding(Matlin 1982; Yoshimura and Ohnishi 1984). In tissue culture cellsinfluenza virus makes use of three different types of cellularprocesses; 1) preexisting clathrin coated pits, 2) virus-inducedclathrin coated pits, and 3) endocytosis in vesicles without visiblecoat (Matlin 1982; Sieczkarski and Whittaker 2002; Rust et al. 2004).Video microscopy using fluorescent viruses showed the virus particlesundergoing actin-mediated rapid motion in the cell periphery followed byminus end-directed, microtubule-mediated transport to the perinucleararea of the cell. Live cell imaging indicated that the virus particlesfirst entered a subpopulation of mobile, peripheral early endosomes thatcarry them deeper into the cytoplasm before penetration takes place(Lakadamyali et al. 2003; Rust et al. 2004). The endocytic process isregulated by protein and lipid kinases, the proteasome, as well as byRabs and ubiquitin-dependent sorting factors (Khor et al. 2003;Whittaker 2006).

The membrane penetration step is mediated by low pH-mediated activationof the trimeric, metastable HA, and the conversion of this Type I viralfusion protein to a membrane fusion competent conformation (Maeda et al.1981; White et al. 1982). This occurs about 16 min afterinternalization, and the pH threshold varies between strains in the5.0-5.6 range. The target membrane is the limiting membrane ofintermediate or late endosomes. The mechanism of fusion has beenextensively studied (Kielian and Rey 2006). Further it was observed thatfusion itself does not seem to require any host cell components except alipid bilayer membrane and a functional acidification system (Maeda etal. 1981; White et al. 1982). The penetration step is inhibited byagents such as lysosomotropic weak bases, carboxylic ionophores, andproton pump inhibitors (Matlin 1982; Whittaker 2006).

To allow nuclear import of the incoming vRNPs, the capsid has to bedisassembled. This step involves acidification of the viral interiorthrough the amantadine-sensitive M2-channels causes dissociation ofMlfrom the vRNPs (Bukrinskaya et al. 1982; Martin and Helenius 1991;Pinto et al. 1992). Transport of the individual vRNPs to the nuclearpore complexes and transfer into the nucleus depends on cellular nucleartransport receptors (O'Neill et al. 1995; Cros et al. 2005). Replicationof the viral RNAs (synthesis of positive and negative strands), andtranscription occurs in complexes tightly associated with the chromatinin the nucleus. It is evident that, although many of the steps arecatalyzed by the viral polymerase, cellular factors are involvedincluding RNA polymerase activating factors, a chaperone HSP90, hCLE,and a human splicing factor UAP56. Viral gene expression is subject tocomplex cellular control at the transcriptional level, a control systemdependent on cellular kinases (Whittaker 2006).

The final assembly of an influenza particle occurs during a buddingprocess at the plasma membrane. In epithelial cells, budding occurs atthe apical membrane domain only (Rodriguez-Boulan 1983). First, theprogeny vRNPs are transported within the nucleoplasm to the nuclearenvelope, then from the nucleus to the cytoplasm, and finally theyaccumulate in the cell periphery. Exit from the nucleus is dependent onviral protein NEP and M1, and a variety of cellular proteins includingCRM1 (a nuclear export receptor), caspases, and possibly some nuclearprotein chaperones. Phosphorylation plays a role in nuclear export byregulating M1 and NEP synthesis, and also through the MAPK/ERK system(Bui et al. 1996; Ludwig 2006). G protein and protein kinase signalingis involved in influenza virus budding from infected host cells (Hui E.and Nayak D, 2002).

The three membrane proteins of the virus are synthesized, folded andassembled into oligomers in the ER (Doms et al. 1993). They pass throughthe Golgi complex; undergo maturation through modification of theircarbohydrate moieties and proteolytic cleavage. After reaching theplasma membrane they associate with M1 and the vRNPs in a buddingprocess that results in the inclusion of all eight vRNPs and exclusionof most host cell components except lipids.

Influenza infection is associated with activation of several signalingcascades including the MAPK pathway (ERK, JNK, p38 and BMK-1/ERK5), theIkB/NF-kB signaling module, the Raf/MEK/ERK cascade, and programmed celldeath (Ludwig 2006). These result in a variety of effects that limit theprogress of infection such as transcriptional activation of IFNb,apoptotic cell death, and a block in virus escape of from late endosomes(Ludwig 2006).

Most previous studies on virus-cell interactions were performed intissue culture using tissue culture- or egg-adapted virus strains. Theviruses in these examples were adapted in such as manner that changeswere induced that affected receptor binding and tropism (Matrosovich2006). Infection with wild-type pathogenic strains is provides a morenatural picture of viral interaction with host proteins. It is knownthat in the human airways influenza A and B primarily infect nonciliated epithelial cells in the upper respiratory track carrying NeuSAca-(2,6)-Gal, whereas avian strains infect ciliated epithelial cell witha-(2,3)-linked sialic acids deeper in the airways (Matrosovich et al.2004a).

Additionally, progress has been made in the elucidation of the stepsinvolved during infection by HRV of host cells. Selected events inrhinovirus infection of the normal human airway can be regarded asoccurring sequentially. Initial steps in rhinovirus pathogenesis arebelieved to include viral entry through the nose, mucociliary transportof virus to the posterior pharynx, and initiation of infection inciliated and non-ciliated epithelial cells of the upper airway. Viralreplication peaks on average within 48 h of initiation of infection andpersists for up to 3 wk. Infection is followed by activation of severalinflammatory mechanisms, which can include release or generation ofinterleukins, bradykinins, prostaglandins, and possibly histamine andstimulation of parasympathetic reflexes. Pathophysiologic processes areinitiated, which include vasodilatation of nasal blood vessels,transudation of plasma, glandular secretion, and stimulation of nervefibers, causing pain and triggering sneeze and cough reflexes. Theresultant clinical illness is a rhinosinusitis, pharyngitis, andbronchitis, which, on average, lasts one week.

Changes in gene expression profiles during in vivo rhinovirus infectionshave been identified (Proud D. et al. Am J Respir Crit. Care Med Vol178. pp 962-968, 2008). Nasal epithelial scrapings were obtained beforeand during experimental rhinovirus infection, and gene expression wasevaluated by microarray. Viperin is identified as an antiviral proteininduced by interferon (IFN), viral infections, and pathogen-associatedmolecules. Naturally acquired rhinovirus infections, cultured humanepithelial cells, and short interfering RNA knockdown were used tofurther evaluate the role of viperin in rhinovirus infections. Symptomscores and viral titers were measured in subjects inoculated withrhinovirus or a sham control, and changes in gene expression wereassessed 8 and 48 hours after inoculation. Rhinovirus-induced changes ingene expression were not observed 8 hours after viral infection, but11,887 gene transcripts were significantly altered in scrapings obtained2 days post-inoculation. Major groups of up-regulated genes includechemokines, signaling molecules, interferon-responsive genes, andantivirals. Rhinovirus infection significantly alters the expression ofmany genes associated with the immune response, including chemokines andantivirals. Some of the genes markedly induced by HRV-16 infectioninclude but are not limited to CCL2, CCL8, CXCL11, CXCL10, CXCL13,CXCL9, CCL20, IFIT2, GBP1, IFIT1, GIP2, IFIT4, IL28B, IRF7, CIG5, NOS2A,OAS3, OASL, OAS2, OAS1, MX2, MX1, PLSCR1, SOCS1, SOCS2, MDA5, RIGI,SOCS3, ICAM-1, HAPLN3, MMP12, EPSTI1, and TNC.

Fatty Acid Synthesis Pathway

Various aspects of the present disclosure relate to compositions andmethods that modulate the activity of the fatty acid synthesis pathwayto treat a viral infection or treat cancer. The fatty acid synthesispathway in humans can use four enzymes: 1) acetyl-CoA carboxylase (ACC),which can synthesize malonyl-CoA; 2) malic enzyme, which can produceNADPH; 3) citrate lyase, which can synthesize acetyl-CoA; and 4) fattyacid synthase, which can catalyze NADPH-dependent synthesis of fattyacids from acetyl-CoA and malonyl-CoA. In various aspects, the presentdisclosure relates to treatment of viral infections and cancer bymodulating the activity of the fatty acid synthase protein.

The final products of fatty acid synthase are free fatty acids which canuse separate enzymatic derivatization with coenzyme-A for incorporationinto other products. In humans, fatty acid synthesis can occur in twosites: the liver, where palmitic acid can be made (Roncari, (1974) Can.J. Biochem., 52:221-230) and lactating mammary gland, where C₁₀-C₁₄fatty acids can be made (Thompson, et al., (1985) Pediatr. Res.,19:139-143).

Fatty acids can be synthesized in the cytoplasm from acetyl-CoA.Acetyl-CoA can be generated from pyruvate by pyruvate dehyrodenase (PDH)and by β-oxidation of fatty acids in the mitochondria. A “citrateshuttle” can transport acetyl-CoA from the mitochondria to thecytoplasm. Acetyl-CoA can react with oxaloacetate to yield citrate, anda tricarboxylate translocase can transport citrate from the mitochondriato the cytosol. In the cytoplasm, citrate can be cleaved back tooxaloacetate and acetyl-CoA, a reaction that can be catalyzed byATP-citrate lyase. Oxaloacetate can be converted back to pyruvate forre-entry into mitochondria.

Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC)is a complex multifunctional, biotin-containing, enzyme system that cancatalyze carboxylation of acetyl-CoA to malonyl-CoA. This conversion isan irreversible, rate-limiting step in fatty acid synthesis. ACC cancarry out three functions: biotin carboxyl carrier protein, biotincarboxylase and carboxyltransferase. ATP-dependent carboxylation ofbiotin, a prosthetic group (cofactor) can be followed by transfer of thecarboxyl group to acetyl-CoA.

HCO₃ ⁻+ATP+acetyl-CoA→ADP+P_(i)+malonyl-CoA

There are two ACC forms, alpha and beta, encoded by two different genesACC-alpha (also known as ACC, ACAC, ACC1, ACCA, and ACACA) can encodeprotein highly enriched in lipogenic tissues. Multiple alternativelyspliced transcript variants divergent in the sequence and encodingdistinct isoforms have been found for this gene. ACC-beta (also known asACC2, ACCB, HACC275, and ACACB) can encode protein thought to controlfatty acid oxidation by means of the ability of malonyl-CoA to inhibitcarnitine-palmitoyl-CoA transferase I, the rate-limiting step in fattyacid uptake and oxidation by mitochondria. ACC-beta may be involved inthe regulation of fatty acid oxidation, rather than fatty acidbiosynthesis. There is evidence for the presence of two ACC-betaisoforms.

ACC can be regulated by the phosphorylation/dephosphorylation oftargeted serine residues. For example, AMP-activated kinase (AMPK) canphosphorylate ACC, and this phosphorylation can inhibit the ability ofACC to produce malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79,Ser1200, and Ser1215 (Park S. H. et al. (2002) J. Appl. Physiol.92:2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie D. G. (1992)Biochim. Biophys. Acta 1123:231-8). Also, cAMP-dependent protein kinase(Protein Kinase A, or PKA) can phosphorylate ACC.

ACC can be regulated by allosteric transformation by citrate orpalmitoyl-CoA. For example, citrate can be a positive effector (i.e.citrate can allosterically activate ACC). Citrate concentration can behigh when there is adequate acetyl-CoA entering the Krebs Cycle. Excessaceytl-CoA can then be converted via malonyl-CoA to fatty acids.Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA, which is theproduct of Fatty Acid Synthase (FASN), can promote the inactiveconformation of ACC, which can reduce production of malonyl-CoA (afeedback inhibition process). AMP can regulate fatty acid synthesis byregulating the availability of malonyl-CoA. Insulin binding a receptorcan activate a phosphatase to dephosphorylate ACC, which can remove theinhibitory effect.

The fatty acid synthase gene (also known as FAS, OA-519, SDR27X1;MGC14367; MGC15706; FASN) is involved in fatty acid synthesis. Theenzyme encoded by this gene is a multifunctional protein ofapproximately 272 kDa with multiple domains, each with distinct enzymeactivities that can play a role in fatty acid biosynthesis. FASN cancatalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, inthe presence of NADPH, into long-chain saturated fatty acids. In somecancer cell lines, FASN protein has been found to be fused with estrogenreceptor-alpha (ER-alpha), in which the N-terminus of FASN is fusedin-frame with the C-terminus of ER-alpha.

FASN protein can exist in the cytosol as a dimer of identical subunits.FASN consists of three catalytic domains in the N-terminal section(-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase(DH)). The N-terminal section is separated by a core region of about 600amino acids from four C-terminal domains (enoyl reductase (ER),-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase(TE)). The crystal structure of a mammalian fatty acid synthase has beenreported (Maier T. et al. (2008) Science 321: 1315-1322). Each of thecatalytic domains of FASN can be targeted in the methods of treatingviral infection of the provided invention.

The enzymatic steps of fatty acid synthesis can involve decarboxylativecondensation, reduction, dehydration, and another reduction and canresult in a saturated acyl moiety. NADPH can be an electron donor inreductive reactions.

Antiviral Activity

In various aspects, the present disclosure provides methods for treatingviral infection in a subject, the method comprising administering to asubject in need of such treatment an effective amount of a compound ofStructures (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1.

In various aspects, the disclosure provides methods for treating a viralinfection, the method comprising administering the compounds of thepresent disclosure to a subject in need thereof the agent.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat influenza infection,adenovirus infection, respiratory syncytial virus infection, poxvirusinfection, poliomyelitis infection, hepatitis C infection, yellow feverinfection, dengue fever infection, rhinovirus infection, and the like.

In various aspects, the present disclosure provides methods for treatinghepatitis C infection by administering to the subject one or morecompounds disclosed herein. In modulating the FASN pathway in thesubject, hepatitis C infection is treated. It has been shown thatexpression of FASN is upregulated in human hepatoma cell line Huh7 whenthese cells are infected with HCV. Inhibiting FASN production with aFASN inhibitor reduced the production of HCV. Thus administration to asubject of the compounds of the present disclosure. (Yang, W. et al.(2008) Hepatology 48(5):1396-1403). It is demonstrated in the EXAMPLESthat FASN inhibition correlates to inhibition of HCV.

In certain aspects, the methods of inhibiting viral infection can beperformed in vitro. In further aspects, the methods of inhibiting viralinfection can be performed in vivo.

In certain aspects the compounds of the present disclosure may be usedin combination with other antiviral treatments in the treating of viralinfection.

In various aspects, the viral infection is a human yellow feverinfection. In further aspects, the viral infection is a human hepatitisC infection. In yet further aspects, the viral infection is a humanrhinoviral infection.

In various aspects the compounds of the present disclosure can be usedfor the treatment of infection of an animal subject, such as a human, byany of a plethora of viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the inhibition of a host by a respiratory virus. Respiratory virusesare most commonly transmitted by airborne droplets or nasal secretionsand can lead to a wide spectrum of illness. Respiratory viruses includethe respiratory syncytial virus (RSV), influenza viruses, coronavirusessuch as SARS, adenoviruses, parainfluenza viruses and rhinoviruses(HRV).

According to one aspect, the present disclosure can be used to treatinfection by HRV. The genus of rhinoviruses is a member of thePicornaviridae family of viruses. Genera within the family include theGenus Enterovirus, Rhinovirus, Cardiovirus, Aphthovirus, Hepatovirus,Parechovirus, Erbovirus, Kobuvirus, Teschovirus. Human rhinoviruses(HRV) include the most common viruses that infect humans and can causethe common cold. HRV are lytic in nature. Rhinoviruses havesingle-stranded positive sense RNA genomes of between 7.2 and 8.5 kb inlength. At the 5′ end of these genomes is a virus-encoded protein, andlike mammalian mRNA, there is also a 3′ poly-A tail. The 5′-terminal UMPof the viral RNA is covalently linked to the small viral protein VPg(Paul A V, et al. Nature 1998, 393(6682):280-284). The 5′UTR containstwo structural elements. One is the 5′-cloverleaf structure involved inthe plus-strand RNA synthesis and in the process of switching fromtranslation to replication (Huang H, et al. Biochemistry 2001,40(27):8055-8064). The other is the internal ribosomal entry site (IRES)which promotes translation of the polyprotein. In addition,species-specific internal cis-acting replication elements (cre) havebeen identified in human enteroviruses (HEV), HRV-A and HRV-B (Gerber K,Wimmer E, Paul A V, J Virol 2001, 75(22):10979-10990). The viralparticles themselves are not enveloped and are icosahedral in structure.Rhinoviruses also grow best in temperatures between 33-35° C. They arealso sensitive to acidic environment.

HRV viral proteins are transcribed as a single long polypeptide, whichis cleaved into the viral structural and nonstructural proteins.Rhinoviruses are composed of a capsid that contains four viral proteinsVP1, VP2, VP3 and VP4 (Rossmann M, et al. 1985 Nature 317 (6033):145-53; Smith T, et al. 1986, Science 233 (4770): 1286-93). Theisometric nucleocapsids are 22-40 nm in diameter. VP1, VP2, and VP3 formthe major part of the protein capsid. The much smaller VP4 protein has amore extended structure and lies at interface between the capsid and theRNA genome. There are 60 copies of each of these proteins assembled asan icosahedron. Human antibodies that target epitopes lying on theexterior regions of VP1-VP3 play a role in the immune response to HRVs.

HRVs have two general modes of transmission: 1) via aerosols ofrespiratory droplets and 2) from contaminated surfaces, including directperson-to-person contact. The primary route of entry for rhinoviruses isthe upper respiratory tract. Afterwards, an HRV binds to ICAM-1(Inter-Cellular Adhesion Molecule 1) also known as CD54 (Cluster ofDifferentiation 54) receptors on respiratory epithelial cells. As thevirus replicates and spreads, infected cells release chemokines andcytokines, which in turn activate inflammatory mediators. Infectionoccurs rapidly, with the rhinovirus adhering to surface receptors within15 minutes of entering the respiratory tract. The incubation period isgenerally 8-10 hours before symptoms begin to occur. HRVs are the mostfrequent cause of infection across all age groups of the humanpopulation. Replication is often restricted to the upper respiratorytract leading to self-limited illnesses such as the common cold.However, HRV infections can also exacerbate pre-existing airwaydisorders, invade the lower respiratory tract and lead to seriouscomplications.

In another aspect, the compounds of the present disclosure can be usedfor the treatment of infection by the influenza virus by targeting thepathways that the virus relies on for infection or replication.Influenza viruses belong to Orthomyxoviridae family of viruses. Thisfamily also includes Thogoto viruses and Dhoriviruses. There are severaltypes and subtypes of influenza viruses known, which infect humans andother species. Influenza type A viruses infect people, birds, pigs,horses, seals and other animals, but wild birds are the natural hostsfor these viruses. Influenza type A viruses are divided into subtypesand named on the basis of two proteins on the surface of the virus:hemagglutinin (HA) and neuraminidase (NA). For example, an “H7N2 virus”designates an influenza A subtype that has an HA 7 protein and an NA 2protein. Similarly an “H5N1” virus has an HA 5 protein and an NA 1protein. There are 16 known HA subtypes and 9 known NA subtypes. Manydifferent combinations of HA and NA proteins are possible. Only someinfluenza A subtypes (i.e., H1N1, H1N2, and H3N2) are currently ingeneral circulation among people. Other subtypes are found most commonlyin other animal species. For example, H7N7 and H3N8 viruses causeillness in horses, and H3N8 also has recently been shown to causeillness in dogs (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Antiviral agents which target host cell proteins involved in influenzainfection can be used to protect high-risk groups (hospital units,institutes caring for elderly, immuno-suppressed individuals), and on acase by case basis. A potential use for antiviral agents is to limit thespread and severity of the future pandemics whether caused by avian H5N1or other strains of influenza virus. Avian influenza A viruses of thesubtypes H5 and H7, including H5N1, H7N7, and H7N3 viruses, have beenassociated with high pathogenicity, and human infection with theseviruses have ranged from mild (H7N3, H7N7) to severe and fatal disease(H7N7, H5N1). Human illness due to infection with low pathogenicityviruses has been documented, including very mild symptoms (e.g.,conjunctivitis) to influenza-like illness. Examples of low pathogenicityviruses that have infected humans include H7N7, H9N2, and H7N2 (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza B viruses are usually found in humans but can also infectseals. Unlike influenza A viruses, these viruses are not classifiedaccording to subtype. Influenza B viruses can cause morbidity andmortality among humans, but in general are associated with less severeepidemics than influenza A viruses. Although influenza type B virusescan cause human epidemics, they have not caused pandemics. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza type C viruses cause mild illness in humans and do not causeepidemics or pandemics. These viruses can also infect dogs and pigs.These viruses are not classified according to subtype. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza viruses differ from each other in respect to cell surfacereceptor specificity and cell tropism, however they use common entrypathways. The compounds of the present disclosure advantageously targetpathways that are common to multiple viruses giving rise to broaderantiviral activity. Thus, the present compounds can also prove usefulagainst unrelated viruses that use similar pathways. For example, theagents can protect airway epithelial cells against a number of differentviruses in addition to influenza viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by adenoviruses. Most adenovirusescommonly cause respiratory illness; symptoms of respiratory illnesscaused by adenovirus infection range from the common cold syndrome topneumonia, croup, and bronchitis. Patients with compromised immunesystems are especially susceptible to severe complications of adenovirusinfection. Acute respiratory disease (ARD), first recognized amongmilitary recruits during World War II, can be caused by adenovirusinfections during conditions of crowding and stress. Adenoviruses aremedium-sized (90-100 nm), nonenveloped icosohedral viruses containingdouble-stranded DNA. There are 49 immunologically distinct types (6subgenera: A through F) that can cause human infections. Adenovirusesare unusually stable to chemical or physical agents and adverse pHconditions, allowing for prolonged survival outside of the body. Someadenoviruses, such as AD2 and Ad5 (species C) use clathrin mediatedendocytosis and macropinocytosis for infectious entry. Otheradenoviruses, such as Ad3 (species B) use dynamin dependent endocytosisand macropinocytosis for infectious entry.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by respiratory syncytial virus (RSV). RSVis the most common cause of bronchiolitis and pneumonia among infantsand children under 1 year of age. Illness begins most frequently withfever, runny nose, cough, and sometimes wheezing. During their first RSVinfection, between 25% and 40% of infants and young children have signsor symptoms of bronchiolitis or pneumonia, and 0.5% to 2% requirehospitalization. Most children recover from illness in 8 to 15 days. Themajority of children hospitalized for RSV infection are under 6 monthsof age. RSV also causes repeated infections throughout life, usuallyassociated with moderate-to-severe cold-like symptoms; however, severelower respiratory tract disease can occur at any age, especially amongthe elderly or among those with compromised cardiac, pulmonary, orimmune systems. RSV is a negative-sense, enveloped RNA virus. The virionis variable in shape and size (average diameter of between 120 and 300nm), is unstable in the environment (surviving only a few hours onenvironmental surfaces), and is readily inactivated with soap and waterand disinfectants.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by human parainfluenza virus (HPIV).HPIVs are second to respiratory syncytial virus (RSV) as a common causeof lower respiratory tract disease in young children. Similar to RSV,HPIVs can cause repeated infections throughout life, usually manifestedby an upper respiratory tract illness (e.g., a cold and/or sore throat).HPIVs can also cause serious lower respiratory tract disease with repeatinfection (e.g., pneumonia, bronchitis, and bronchiolitis), especiallyamong the elderly, and among patients with compromised immune systems.Each of the four HPIVs has different clinical and epidemiologicfeatures. The most distinctive clinical feature of HPIV-1 and HPIV-2 iscroup (i.e., laryngotracheobronchitis); HPIV-1 is the leading cause ofcroup in children, whereas HPIV-2 is less frequently detected. BothHPIV-1 and -2 can cause other upper and lower respiratory tractillnesses. HPIV-3 is more often associated with bronchiolitis andpneumonia. HPIV-4 is infrequently detected, possibly because it is lesslikely to cause severe disease. The incubation period for HPIVs isgenerally from 1 to 7 days. HPIVs are negative-sense, single-strandedRNA viruses that possess fusion and hemagglutinin-neuraminidaseglycoprotein “spikes” on their surface. There are four serotypes typesof HPIV (1 through 4) and two subtypes (4a and 4b). The virion varies insize (average diameter between 150 and 300 nm) and shape, is unstable inthe environment (surviving a few hours on environmental surfaces), andis readily inactivated with soap and water.

In various aspects, the compounds of the present disclosure can be usedfor the treatment of infection by coronavirus. Coronavirus is a genus ofanimal virus belonging to the family Coronaviridae. Coronaviruses areenveloped viruses with a positive-sense single-stranded RNA genome and ahelical symmetry. The genomic size of coronaviruses ranges fromapproximately 16 to 31 kilobases, extraordinarily large for an RNAvirus. The name “coronavirus” is derived from the Latin corona, meaningcrown, as the virus envelope appears under electron microscopy to becrowned by a characteristic ring of small bulbous structures. Thismorphology is actually formed by the viral spike peplomers, which areproteins that populate the surface of the virus and determine hosttropism. Coronaviruses are grouped in the order Nidovirales, named forthe Latin nidus, meaning nest, as all viruses in this order produce a 3′co-terminal nested set of subgenomic mRNA's during infection. Proteinsthat contribute to the overall structure of all coronaviruses are thespike, envelope, membrane and nucleocapsid. In the specific case of SARSa defined receptor-binding domain on S mediates the attachment of thevirus to its cellular receptor, angiotensin-converting enzyme 2.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat infections caused byAbelson leukemia virus, Abelson murine leukemia virus, Abelson's virus,Acute laryngotracheobronchitis virus, Adelaide River virus, Adenoassociated virus group, Adenovirus, African horse sickness virus,African swine fever virus, AIDS virus, Aleutian mink disease parvovirus,Alpharetrovirus, Alphavirus, ALV related virus, Amapari virus,Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, arbovirus group A,arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus,Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, Atelineherpesvirus group, Aujezky's disease virus, Aura virus, Ausduk diseasevirus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosisvirus, avian infectious bronchitis virus, avian leukemia virus, avianleukosis virus, avian lymphomatosis virus, avian myeloblastosis virus,avian paramyxovirus, avian pneumoencephalitis virus, avianreticuloendotheliosis virus, avian sarcoma virus, avian type Cretrovirus group, Avihepadnavirus, Avipoxvirus, B virus, B19 virus,Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus,Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, Bittner virus,BK virus, Black Creek Canal virus, bluetongue virus, Bolivianhemorrhagic fever virus, Boma disease virus, border disease of sheepvirus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus2, bovine coronavirus, bovine ephemeral fever virus, bovineimmunodeficiency virus, bovine leukemia virus, bovine leukosis virus,bovine mammillitis virus, bovine papillomavirus, bovine papularstomatitis virus, bovine parvovirus, bovine syncytial virus, bovine typeC oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bulletshaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt'slymphoma virus, Bwamba Fever, CA virus, Calicivirus, Californiaencephalitis virus, camelpox virus, canarypox virus, canid herpesvirus,canine coronavirus, canine distemper virus, canine herpesvirus, canineminute virus, canine parvovirus, Cano Delgadito virus, caprine arthritisvirus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus,Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1,cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Chandipuravirus, Changuinola virus, channel catfish virus, Charleville virus,chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chubreovirus, chum salmon virus, Cocal virus, Coho salmon reovirus, coitalexanthema virus, Colorado tick fever virus, Coltivirus, Columbia SKvirus, common cold virus, contagious eethyma virus, contagious pustulardermatitis virus, Coronavirus, Corriparta virus, coryza virus, cowpoxvirus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricketparalysis virus, Crimean-Congo hemorrhagic fever virus, croup associatedvirus, Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group,cytoplasmic polyhedrosis virus, deer papillomavirus, deltaretrovirus,dengue virus, Densovirus, Dependovirus, Dhori virus, diploma virus,Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1, duckhepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV,eastern equine encephalitis virus, eastern equine encephalomyelitisvirus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus,echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus,EIA virus, EIA virus, encephalitis virus, encephalomyocarditis groupvirus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus,enzyme elevating virus (LDH), epidemic hemorrhagic fever virus,epizootic hemorrhagic disease virus, Epstein-Barr virus, equidalphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2,equine abortion virus, equine arteritis virus, equine encephalosisvirus, equine infectious anemia virus, equine morbillivirus, equinerhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elkpapillomavirus, European swine fever virus, Everglades virus, Eyachvirus, felid herpesvirus 1, feline calicivirus, feline fibrosarcomavirus, feline herpesvirus, feline immunodeficiency virus, felineinfectious peritonitis virus, feline leukemia/sarcoma virus, felineleukemia virus, feline panleukopenia virus, feline parvovirus, felinesarcoma virus, feline syncytial virus, Filovirus, Flanders virus,Flavivirus, foot and mouth disease virus, Fort Morgan virus, FourCorners hantavirus, fowl adenovirus 1, fowlpox virus, Friend virus,Gammaretrovirus, GB hepatitis virus, GB virus, German measles virus,Getah virus, gibbon ape leukemia virus, glandular fever virus, goatpoxvirus, golden shinner virus, Gonometa virus, goose parvovirus,granulosis virus, Gross' virus, ground squirrel hepatitis B virus, groupA arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pigtype C virus, Hantaan virus, Hantavirus, hard clam reovirus, harefibroma virus, HCMV (human cytomegalovirus), hemadsorption virus 2,hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus,Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group,hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis Evirus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus,hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitisreovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, herpessimplex virus, herpes simplex virus 1, herpes simplex virus 2,herpesvirus, herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis,Herpesvirus infection, Herpesvirus saimiri, Herpesvirus suis,Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, hogcholera virus, human adenovirus 2, human alphaherpesvirus 1, humanalphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropicvirus, human betaherpesvirus 5, human coronavirus, human cytomegalovirusgroup, human foamy virus, human gammaherpesvirus 4, humangammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group,human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus4 group, human herpesvirus 6, human herpesvirus 8, humanimmunodeficiency virus, human immunodeficiency virus 1, humanimmunodeficiency virus 2, human papillomavirus, human T cell leukemiavirus, human T cell leukemia virus I, human T cell leukemia virus II,human T cell leukemia virus III, human T cell lymphoma virus I, human Tcell lymphoma virus II, human T cell lymphotropic virus type 1, human Tcell lymphotropic virus type 2, human T lymphotropic virus I, human Tlymphotropic virus II, human T lymphotropic virus III, Ichnovirus,infantile gastroenteritis virus, infectious bovine rhinotracheitisvirus, infectious haematopoietic necrosis virus, infectious pancreaticnecrosis virus, influenza virus A, influenza virus B, influenza virus C,influenza virus D, influenza virus pr8, insect iridescent virus, insectvirus, iridovirus, Japanese B virus, Japanese encephalitis virus, JCvirus, Junin virus, Kaposi's sarcoma-associated herpesvirus, Kemerovovirus, Kilham's rat virus, Klamath virus, Kolongo virus, Koreanhemorrhagic fever virus, kumba virus, Kysanur forest disease virus,Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus,lactic dehydrogenase virus, Lagos bat virus, Langur virus, lapineparvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM virus,Leaky virus, Lentivirus, Leporipoxyirus, leukemia virus, leukovirus,lumpy skin disease virus, lymphadenopathy associated virus,Lymphocryptovirus, lymphocytic choriomeningitis virus,lymphoproliferative virus group, Machupo virus, mad itch virus,mammalian type B oncovirus group, mammalian type B retroviruses,mammalian type C retrovirus group, mammalian type D retroviruses,mammary tumor virus, Mapuera virus, Marburg virus, Marburg-like virus,Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus,measles virus, Menangle virus, Mengo virus, Mengovirus, Middelburgvirus, milkers nodule virus, mink enteritis virus, minute virus of mice,MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscumcontagiosum virus, monkey B virus, monkeypox virus, Mononegavirales,Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouseencephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouseleukemia virus, mouse mammary tumor virus, mouse minute virus, mousepneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mousesarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosaldisease virus, mumps virus, murid betaherpesvirus 1, muridcytomegalovirus 2, murine cytomegalovirus group, murineencephalomyelitis virus, murine hepatitis virus, murine leukemia virus,murine nodule inducing virus, murine polyomavirus, murine sarcoma virus,Muromegalovirus, Murray Valley encephalitis virus, myxoma virus,Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheepdisease virus, Nairovirus, Nanirnavirus, Nariva virus, Ndumo virus,Neethling virus, Nelson Bay virus, neurotropic virus, New WorldArenavirus, newborn pneumonitis virus, Newcastle disease virus, Nipahvirus, noncytopathogenic virus, Norwalk virus, nuclear polyhedrosisvirus (NPV), nipple neck virus, O'nyong'nyong virus, Ockelbo virus,oncogenic virus, oncogenic viruslike particle, oncornavirus, Orbivirus,Orf virus, Oropouche virus, Orthohepadnavirus, Orthomyxovirus,Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovinecatarrhal fever virus, owl monkey herpesvirus, Palyam virus,Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenzavirus, parainfluenza virus type 1, parainfluenza virus type 2,parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus,Parapoxvirus, paravaccinia virus, Parvovirus, Parvovirus B19, parvovirusgroup, Pestivirus, Phlebovirus, phocine distemper virus, Picodnavirus,Picornavirus, pig cytomegalovirus—pigeonpox virus, Piry virus, Pixunavirus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus,poliovirus, Polydnavirus, polyhedral virus, polyoma virus, Polyomavirus,Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2,Polyomavirus maccacae 1, Polyomavirus muris 1, Polyomavirus muris 2,Polyomavirus papionis 1, Polyomavirus papionis 2, Polyomavirussylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus,porcine hemagglutinating encephalomyelitis virus, porcine parvovirus,porcine transmissible gastroenteritis virus, porcine type C virus, poxvirus, poxvirus, poxvirus variolae, Prospect Hill virus, Provirus,pseudocowpox virus, pseudorabies virus, psittacinepox virus, quailpoxvirus, rabbit fibroma virus, rabbit kidney vaculolating virus, rabbitpapillomavirus, rabies virus, raccoon parvovirus, raccoonpox virus,Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus,Rauscher's virus, recombinant vaccinia virus, recombinant virus,reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C virus,respiratory infection virus, respiratory syncytial virus, respiratoryvirus, reticuloendotheliosis virus, Rhabdovirus, Rhabdovirus carpia,Rhadinovirus, Rhinovirus, Rhizidiovirus, Rift Valley fever virus,Riley's virus, rinderpest virus, RNA tumor virus, Ross River virus,Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeolavirus, Rubivirus, Russian autumn encephalitis virus, SA 11 simian virus,SA2 virus, Sabia virus, Sagiyama virus, Saimirine herpesvirus 1,salivary gland virus, sandfly fever virus group, Sandjimba virus, SARSvirus, SDAV (sialodacryoadenitis virus), sealpox virus, Semliki ForestVirus, Seoul virus, sheeppox virus, Shope fibroma virus, Shope papillomavirus, simian foamy virus, simian hepatitis A virus, simian humanimmunodeficiency virus, simian immunodeficiency virus, simianparainfluenza virus, simian T cell lymphotrophic virus, simian virus,simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpoxvirus, South American hemorrhagic fever viruses, sparrowpox virus,Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1virus group, STLV (simian T lymphotropic virus) type I, STLV (simian Tlymphotropic virus) type II, STLV (simian T lymphotropic virus) typeIII, stomatitis papulosa virus, submaxillary virus, suidalphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus,swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complexvirus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus,Theiler's encephalomyelitis virus, Theiler's virus, Thogoto virus,Thottapalayam virus, Tick borne encephalitis virus, Tioman virus,Togavirus, Torovirus, tumor virus, Tupaia virus, turkey rhinotracheitisvirus, turkeypox virus, type C retroviruses, type D oncovirus, type Dretrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemivirus group, vaccinia virus, vacuolating virus, varicella zoster virus,Varicellovirus, Varicola virus, variola major virus, variola virus,Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitisvirus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagicfever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus,viper retrovirus, viral haemorrhagic septicemia virus, Visna Maedivirus, Visna virus, volepox virus, VSV (vesicular stomatitis virus),Wallal virus, Warrego virus, wart virus, WEE virus, West Nile virus,western equine encephalitis virus, western equine encephalomyelitisvirus, Whataroa virus, Winter Vomiting Virus, woodchuck hepatitis Bvirus, woolly monkey sarcoma virus, wound tumor virus, WRSV virus, Yabamonkey tumor virus, Yaba virus, Yatapoxvirus, yellow fever virus, andthe Yug Bogdanovac virus.

Utility in Metabolic Disorders

In various aspects, the compounds of the present disclosure have utilityin the treating of metabolic diseases. FASN has been demonstrated to beinvolved in regulation of glucose, lipids and cholesterol metabolism.Mice with a liver-specific inactivation of FASN have normal physiologyunless fed a zero-fat diet, in which case they develop hypoglycemia andfatty liver, both of which are reversed with dietary fat. (Chakravarthy,M. V., et al. (2005) Cell Metabolism 1:309-322). Db/+ mice fed a highfructose diet exhibit reduced liver triglyceride levels and improvedinsulin sensitivity when treated for 28 days with platensimycin, acovealent inhibitor of FASN. (Wu, M. et al. (2011) PNAS108(13):5378-5383). Ambient glucose levels are also reduced in db/dbmice following treatment with platensimycin. These results provideevidence that inhibiting FASN can yield therapeutically relevantbenefits in animal models of diabetes and related metabolic disorders.Thus the disclosed FASN inhibitors are useful in the treatment ofdisorders characterized by disregulation in these systems. Withoutlimitation, examples include steatosis and diabetes.

Anticancer Activity

In various aspects, the present disclosure provides methods for treatingcancer in subject, the method comprising administering to a subject inneed of such treatment an effective amount of a compound of Structures(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1. In further aspects, compounds having Structure (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1 can be used for the manufacture of a medicament fortreating cancer.

In certain aspects, the present disclosure provides a method forinhibiting tumor cell growth in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Structure (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1. In further aspects,the tumor can be derived from ovary, breast, lung, thyroid, lymph node,kidney, ureter, bladder, ovary, teste, prostate, bone, skeletal muscle,bone marrow, stomach, esophagus, small bowel, colon, rectum, pancreas,liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx,oropharynx, salivary gland, or heart tissue. In certain aspects, thepresent compounds can be administered concurrently with one or moreadditional anti-cancer treatments.

Rapidly proliferating cancer cells activate the fatty acid synthesispathway to supply the high levels of lipids needed for membrane assemblyand oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology.6(4):551-562) Inhibitors of fatty acid synthesis have demonstrated invivo activity in preclinical cancer models. (Orita, H. et al. (2007)Clinical Cancer Research. 13(23):7139-7145 and Puig, T. et al. (2011)Breast Cancer Research, 13(6):R131) Additionally, fatty acid synthesissupports new blood vessel formation and inhibitors of this pathway haveactivity in in vitro models of angiogenesis. (Browne, C. D., et al.(2006) The FASEB Journal, 20(12):2027-2035). The presently disclosedcompounds demonstrated the ability to selectively induce cell-cyclearrest in HUVEC cells without causing general cell death by apoptosis.See EXAMPLES.

The cancer treatment of the present invention includes an anti-tumoreffect that may be assessed by conventional means such as the responserate, the time to disease progression and/or the survival rate.Anti-tumor effects of the present invention include, but are not limitedto, inhibition of tumor growth, tumor growth delay, regression of tumor,shrinkage of tumor, increased time to regrowth of tumor on cessation oftreatment and slowing of disease progression. For example, it isexpected that when the combination of the present invention isadministered to a warm-blooded animal such as a human, in need oftreatment for cancer involving a solid tumor, such a method of treatmentwill produce an effect, as measured by, for example, one or more of: theextent of the anti-tumor effect, the response rate, the time to diseaseprogression and the survival rate.

Methods of Treatment

Also provided herein are pharmaceutical compositions comprising thecompounds of the present disclosure. The present compositions andmethods have antiviral and/or anticancer activity.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Structures (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In certain aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Table 1 and apharmaceutically acceptable carrier, excipient, or diluent.

Certain aspects of the present disclosure relates to methods of usingpharmaceutical compositions and kits comprising one or more agents thatinhibit the fatty acid synthesis pathway to inhibit or decrease a viralinfection or for the treatment of cancer. Certain aspects of the presentdisclosure relates to methods of using pharmaceutical compositions andkits comprising one or more agents that inhibit fatty acid synthase toinhibit or decrease a viral infection or for the treatment of cancer.Another aspect of the present invention provides methods, pharmaceuticalcompositions, and kits for the treatment of animal subjects having aviral infection or cancer or at risk of developing a viral infection orcancer. The term “subject” as used herein includes humans as well asother mammals. The term “treating” as used herein includes achieving atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying viralinfection. Also, a therapeutic benefit is achieved with the eradicationor amelioration of one or more of the physiological symptoms associatedwith the underlying viral infection such that an improvement is observedin the animal subject, notwithstanding the fact that the subject canstill be afflicted with the underlying virus.

For aspects where a prophylactic benefit is desired, a pharmaceuticalcomposition of the invention can be administered to a patient at risk ofdeveloping viral infection such as HRV, or HIV, or to a patientreporting one or more of the physiological symptoms of a viralinfection, even though a diagnosis of the condition may not have beenmade. Administration can prevent the viral infection from developing, orit can reduce, lessen, shorten and/or otherwise ameliorate the viralinfection that develops. The pharmaceutical composition can modulate thefatty acid synthesis pathway, e.g., FASN gene expression or FASN proteinactivity. Wherein, the term modulate includes inhibition of the fattyacid synthesis pathway, e.g., FASN gene expression or FASN proteinactivity or alternatively activation of the fatty acid synthesispathway, e.g., FASN gene expression or FASN protein activity.

Reducing the activity of the fatty acid synthesis pathway, e.g., FASNgene expression or FASN protein activity, is also referred to as“inhibiting” the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity. The term “inhibits” and itsgrammatical conjugations, such as “inhibitory,” do not require completeinhibition, but refer to a reduction in fatty acid synthesis activity,e.g., FASN gene expression or FASN protein activity. In another aspect,such reduction is by at least 50%, at least 75%, at least 90%, and canbe by at least 95% of the activity of the enzyme in the absence of theinhibitory effect, e.g., in the absence of an inhibitor. Conversely, thephrase “does not inhibit” and its grammatical conjugations refer tosituations where there is less than 20%, less than 10%, and can be lessthan 5%, of reduction in enzyme activity in the presence of the agent.Further the phrase “does not substantially inhibit” and its grammaticalconjugations refer to situations where there is less than 30%, less than20%, and in some aspects less than 10% of reduction in enzyme activityin the presence of the agent.

Increasing the activity of the fatty acid synthesis pathway, e.g., FASNgene expression or FASN protein activity, is also referred to as“activating” the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity. The term “activated” and itsgrammatical conjugations, such as “activating,” do not require completeactivation, but refer to an increase in fatty acid synthesis pathwayactivity, e.g., FASN gene expression or FASN protein activity. Inanother aspect such increase is by at least 50%, at least 75%, at least90%, and can be by at least 95% of the activity of the enzyme in theabsence of the activation effect, e.g., in the absence of an activator.Conversely, the phrase “does not activate” and its grammaticalconjugations refer to situations where there is less than 20%, less than10%, and can be less than 5%, of an increase in enzyme activity in thepresence of the agent. Further the phrase “does not substantiallyactivate” and its grammatical conjugations refer to situations wherethere is less than 30%, less than 20%, and in another aspect less than10% of an increase in enzyme activity in the presence of the agent.

The ability to reduce enzyme activity is a measure of the potency or theactivity of an agent, or combination of agents, towards or against theenzyme. Potency can be measured by cell free, whole cell and/or in vivoassays in terms of IC50, K_(i) and/or ED50 values. An IC50 valuerepresents the concentration of an agent required to inhibit enzymeactivity by half (50%) under a given set of conditions. A K_(i) valuerepresents the equilibrium affinity constant for the binding of aninhibiting agent to the enzyme. An ED50 value represents the dose of anagent required to effect a half-maximal response in a biological assay.Further details of these measures will be appreciated by those ofordinary skill in the art, and can be found in standard texts onbiochemistry, enzymology, and the like.

The present invention also includes kits that can be used to treat viralinfections or treat cancer. These kits comprise an agent or combinationof agents that inhibit the fatty acid synthesis pathway, e.g., FASN geneexpression or FASN protein activity, and optionally instructionsteaching the use of the kit according to the various methods andapproaches described herein. Such kits can also include information,such as scientific literature references, package insert materials,clinical trial results, and/or summaries of these and the like, whichindicate or establish the activities and/or advantages of the agent.Such information can be based on the results of various studies, forexample, studies using experimental animals involving in vivo models andstudies based on human clinical trials. Kits described herein can beprovided, marketed and/or promoted to health providers, includingphysicians, nurses, pharmacists, formulary officials, and the like.

Formulations, Routes of Administration, and Effective Doses

Yet another aspect of the present invention relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising an agent or combination of agents of the instantinvention. Such pharmaceutical compositions can be used to treat viralinfections as described above.

Compounds of the invention can be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, transdermal patch, pulmonary,vaginal, suppository, or parenteral (including intramuscular,intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneousand intravenous) administration or in a form suitable for administrationby aerosolization, inhalation or insufflation. General information ondrug delivery systems can be found in Ansel et al., PharmaceuticalDosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins,Baltimore Md. (1999).

In various aspects, the pharmaceutical composition includes carriers andexcipients (including but not limited to buffers, carbohydrates,mannitol, proteins, polypeptides or amino acids such as glycine,antioxidants, bacteriostats, chelating agents, suspending agents,thickening agents and/or preservatives), water, oils including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like, saline solutions,aqueous dextrose and glycerol solutions, flavoring agents, coloringagents, detackifiers and other acceptable additives, adjuvants, orbinders, other pharmaceutically acceptable auxiliary substances asrequired to approximate physiological conditions, such as pH bufferingagents, tonicity adjusting agents, emulsifying agents, wetting agentsand the like. Examples of excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In another aspect, thepharmaceutical preparation is substantially free of preservatives. Inanother aspect, the pharmaceutical preparation can contain at least onepreservative. General methodology on pharmaceutical dosage forms isfound in Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It willbe recognized that, while any suitable carrier known to those ofordinary skill in the art can be employed to administer the compositionsof this invention, the type of carrier will vary depending on the modeof administration.

Compounds can also be encapsulated within liposomes using well-knowntechnology. Biodegradable microspheres can also be employed as carriersfor the pharmaceutical compositions of this invention. Suitablebiodegradable microspheres are disclosed, for example, in U.S. Pat. Nos.4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883; 5,853,763;5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (ormicroparticles). Methods for preparing liposomes and microspheres foradministration to a patient are well known to those of skill in the art.U.S. Pat. No. 4,789,734, the contents of which are hereby incorporatedby reference, describes methods for encapsulating biological materialsin liposomes. Essentially, the material is dissolved in an aqueoussolution, the appropriate phospholipids and lipids added, along withsurfactants if required, and the material dialyzed or sonicated, asnecessary. A review of known methods is provided by G. Gregoriadis,Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp.2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or proteins are well known to thoseskilled in the art, and can be tailored for passage through thegastrointestinal tract directly into the blood stream. Alternatively,the compound can be incorporated and the microspheres, or composite ofmicrospheres, implanted for slow release over a period of time rangingfrom days to months. See, for example, U.S. Pat. Nos. 4,906,474,4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contentsof which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solutionbuffered and the isotonicity adjusted to be compatible with intravenousinjection, as is well known in the art.

The compounds of the invention can be formulated as a sterile solutionor suspension, in suitable vehicles, well known in the art. Thepharmaceutical compositions can be sterilized by conventional,well-known sterilization techniques, or can be sterile filtered. Theresulting aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration. Suitable formulations and additionalcarriers are described in Remington “The Science and Practice ofPharmacy” (20^(th) Ed., Lippincott Williams & Wilkins, Baltimore Md.),the teachings of which are incorporated by reference in their entiretyherein.

The agents or their pharmaceutically acceptable salts can be providedalone or in combination with one or more other agents or with one ormore other forms. For example a formulation can comprise one or moreagents in particular proportions, depending on the relative potencies ofeach agent and the intended indication. For example, in compositions fortargeting two different host targets, and where potencies are similar,about a 1:1 ratio of agents can be used. The two forms can be formulatedtogether, in the same dosage unit e.g., in one cream, suppository,tablet, capsule, aerosol spray, or packet of powder to be dissolved in abeverage; or each form can be formulated in a separate unit, e.g., twocreams, two suppositories, two tablets, two capsules, a tablet and aliquid for dissolving the tablet, two aerosol sprays, or a packet ofpowder and a liquid for dissolving the powder, etc.

The term “pharmaceutically acceptable salt” means those salts whichretain the biological effectiveness and properties of the agents used inthe present invention, and which are not biologically or otherwiseundesirable. For example, a pharmaceutically acceptable salt does notinterfere with the beneficial effect of an agent of the invention ininhibiting the fatty acid synthesis pathway, e.g., inhibiting FASN geneexpression or FASN protein activity.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the agent(s) contain acarboxy group or other acidic group, it can be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like.

A pharmaceutically acceptable ester or amide refers to those whichretain biological effectiveness and properties of the agents used in thepresent invention, and which are not biologically or otherwiseundesirable. For example, the ester or amide does not interfere with thebeneficial effect of an agent of the invention in inhibiting the fattyacid synthesis pathway, e.g., inhibiting FASN gene expression or FASNprotein activity. Typical esters include ethyl, methyl, isobutyl,ethylene glycol, and the like. Typical amides include unsubstitutedamides, alkyl amides, dialkyl amides, and the like.

In another aspect, an agent can be administered in combination with oneor more other compounds, forms, and/or agents, e.g., as described above.Pharmaceutical compositions comprising combinations of a fatty acidsynthesis pathway inhibitor e.g., an inhibitor or FASN gene expressionor FASN protein activity with one or more other active agents can beformulated to comprise certain molar ratios. For example, molar ratiosof about 99:1 to about 1:99 of a fatty acid synthesis pathway inhibitore.g., an inhibitor of FASN gene expression or FASN protein activity, tothe other active agent can be used. In some subset of the aspects, therange of molar ratios of fatty acid synthesis pathway inhibitor e.g., aninhibitor of FASN gene expression or FASN protein activity: other activeagent is selected from about 80:20 to about 20:80; about 75:25 to about25:75, about 70:30 to about 30:70, about 66:33 to about 33:66, about60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. Themolar ratio of a fatty acid synthesis pathway inhibitor e.g., aninhibitor of FASN gene expression or FASN protein activity: other activeagent can be about 1:9, and in another aspect can be about 1:1. The twoagents, forms and/or compounds can be formulated together, in the samedosage unit e.g., in one cream, suppository, tablet, capsule, or packetof powder to be dissolved in a beverage; or each agent, form, and/orcompound can be formulated in separate units, e.g., two creams,suppositories, tablets, two capsules, a tablet and a liquid fordissolving the tablet, an aerosol spray a packet of powder and a liquidfor dissolving the powder, etc.

If necessary or desirable, the agents and/or combinations of agents canbe administered with still other agents. The choice of agents that canbe co-administered with the agents and/or combinations of agents of theinstant invention can depend, at least in part, on the condition beingtreated. Agents of particular use in the formulations of the presentinvention include, for example, any agent having a therapeutic effectfor a viral infection, including, e.g., drugs used to treat inflammatoryconditions. For example, in treatments for HRV, in some aspectsformulations of the instant invention can additionally contain one ormore conventional anti-inflammatory drugs, such as an NSAID, e.g.,ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin. In somealternative aspects for the treatment of influenza formulations of theinstant invention can additionally contain one or more conventionalinfluenza antiviral agents, such as amantadine, rimantadine, zanamivir,and oseltamivir. In treatments for retroviral infections, such as HIV,formulations of the instant invention can additionally contain one ormore conventional antiviral drug, such as protease inhibitors(lopinavir/ritonavir (Kaletra), indinavir (Crixivan), ritonavir(Norvir), nelfinavir (Viracept), saquinavir hard gel capsules(Invirase), atazanavir (Reyataz), amprenavir (Agenerase), fosamprenavir(Telzir), tipranavir(Aptivus)), reverse transcriptase inhibitors,including non-Nucleoside and Nucleoside/nucleotide inhibitors (AZT(zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine,Epivir), d4T (stavudine, Zerit), abacavir (Ziagen), FTC (emtricitabine,Emtriva), tenofovir (Viread), efavirenz (Sustiva) and nevirapine(Viramune)), fusion inhibitors T20 (enfuvirtide, Fuzeon), integraseinhibitors (MK-0518 and GS-9137), and maturation inhibitors (PA-457(Bevirimat)). As another example, formulations can additionally containone or more supplements, such as vitamin C, E or other anti-oxidants.

In certain aspects, the compounds of the present disclosure can beadministered in combination with a known cancer therapeutic. Forexample, the compounds can be administered in combination withpaclitaxel (commercially available as Taxol, Bristol-Myers Squibb),doxorubicin (also known under the trade name Adriamycin), vincristine(known under the trade names Oncovin, Vincasar PES, and Vincrex),actinomycin D, altretamine, asparaginase, bleomycin, busulphan,capecitabine, carboplatin, carmustine, chlorambucil, cisplatin,cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin,etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea,idarubicin, ifosfamide, irinotecan, lomustine, melphalan,mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin,procarbazine, steroids, streptozocin, taxotere, tamozolomide,thioguanine, thiotepa, tomudex, topotecan, treosulfan, UFT(uracil-tegufur), vinblastine, and vindesine, or the like.

The agent(s) (or pharmaceutically acceptable salts, esters or amidesthereof) can be administered per se or in the form of a pharmaceuticalcomposition wherein the active agent(s) is in an admixture or mixturewith one or more pharmaceutically acceptable carriers. A pharmaceuticalcomposition, as used herein, can be any composition prepared foradministration to a subject. Pharmaceutical compositions for use inaccordance with the present invention can be formulated in conventionalmanner using one or more physiologically acceptable carriers, comprisingexcipients, diluents, and/or auxiliaries, e.g., which facilitateprocessing of the active agents into preparations that can beadministered. Proper formulation can depend at least in part upon theroute of administration chosen. The agent(s) useful in the presentinvention, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a patient using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, the agents can be formulated readily bycombining the active agent(s) with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the agents of the inventionto be formulated as tablets, including chewable tablets, pills, dragees,capsules, lozenges, hard candy, liquids, gels, syrups, slurries,powders, suspensions, elixirs, wafers, and the like, for oral ingestionby a patient to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents. Asolid carrier can be one or more substances which can also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Generally, the agents of the invention will be included at concentrationlevels ranging from about 0.5%, about 5%, about 10%, about 20%, or about30% to about 50%, about 60%, about 70%, about 80% or about 90% by weightof the total composition of oral dosage forms, in an amount sufficientto provide a desired unit of dosage.

Aqueous suspensions for oral use can contain agent(s) of this inventionwith pharmaceutically acceptable excipients, such as a suspending agent(e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithinand/or a long-chain fatty alcohol), as well as coloring agents,preservatives, flavoring agents, and the like.

In another aspect, oils or non-aqueous solvents can be required to bringthe agents into solution, due to, for example, the presence of largelipophilic moieties. Alternatively, emulsions, suspensions, or otherpreparations, for example, liposomal preparations, can be used. Withrespect to liposomal preparations, any known methods for preparingliposomes for treatment of a condition can be used. See, for example,Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc.Natl. Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein byreference. Ligands can also be attached to the liposomes to direct thesecompositions to particular sites of action. Agents of this invention canalso be integrated into foodstuffs, e.g., cream cheese, butter, saladdressing, or ice cream to facilitate solubilization, administration,and/or compliance in certain patient populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate. The agents can also beformulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active agents can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions canbe prepared in solutions, for example, in aqueous propylene glycolsolutions or can contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Suitable fillers or carriers with whichthe compositions can be administered include agar, alcohol, fats,lactose, starch, cellulose derivatives, polysaccharides,polyvinylpyrrolidone, silica, sterile saline and the like, or mixturesthereof used in suitable amounts. Solid form preparations includesolutions, suspensions, and emulsions, and can contain, in addition tothe active component, colorants, flavors, stabilizers, buffers,artificial and natural sweeteners, dispersants, thickeners, solubilizingagents, and the like.

A syrup or suspension can be made by adding the active compound to aconcentrated, aqueous solution of a sugar, e.g., sucrose, to which canalso be added any accessory ingredients. Such accessory ingredients caninclude flavoring, an agent to retard crystallization of the sugar or anagent to increase the solubility of any other ingredient, e.g., as apolyhydric alcohol, for example, glycerol or sorbitol.

When formulating compounds of the invention for oral administration, itcan be desirable to utilize gastroretentive formulations to enhanceabsorption from the gastrointestinal (GI) tract. A formulation which isretained in the stomach for several hours can release compounds of theinvention slowly and provide a sustained release that can be used inmethods of the invention. Disclosure of such gastro-retentiveformulations are found in Klausner, E. A.; Lavy, E.; Barta, M.;Cserepes, E.; Friedman, M.; Hoffman, A. 2003 “Novel gastroretentivedosage forms: evaluation of gastroretentivity and its effect on levodopain humans.” Pharm. Res. 20, 1466-73, Hoffman, A.; Stepensky, D.; Lavy,E.; Eyal, S. Klausner, E.; Friedman, M. 2004 “Pharmacokinetic andpharmacodynamic aspects of gastroretentive dosage forms” Int. J. Pharm.11, 141-53, Streubel, A.; Siepmann, J.; Bodmeier, R.; 2006“Gastroretentive drug delivery systems” Expert Opin. Drug Deliver. 3,217-3, and Chavanpatil, M. D.; Jain, P.; Chaudhari, S.; Shear, R.;Vavia, P. R. “Novel sustained release, swellable and bioadhesivegastroretentive drug delivery system for olfoxacin” Int. J. Pharm. 2006epub March 24. Expandable, floating and bioadhesive techniques can beutilized to maximize absorption of the compounds of the invention.

The compounds of the invention can be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and can be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions can take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol.

For injectable formulations, the vehicle can be chosen from those knownin art to be suitable, including aqueous solutions or oil suspensions,or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil,as well as elixirs, mannitol, dextrose, or a sterile aqueous solution,and similar pharmaceutical vehicles. The formulation can also comprisepolymer compositions which are biocompatible, biodegradable, such aspoly(lactic-co-glycolic)acid. These materials can be made into micro ornanospheres, loaded with drug and further coated or derivatized toprovide superior sustained release performance. Vehicles suitable forperiocular or intraocular injection include, for example, suspensions oftherapeutic agent in injection grade water, liposomes and vehiclessuitable for lipophilic substances. Other vehicles for periocular orintraocular injection are well known in the art.

In a preferred aspect, the composition is formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition can also include a solubilizingagent and a local anesthetic such as lidocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

When administration is by injection, the active compound can beformulated in aqueous solutions, specifically in physiologicallycompatible buffers such as Hanks solution, Ringer's solution, orphysiological saline buffer. The solution can contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the active compound can be in powder form for constitution with asuitable vehicle, e.g., sterile pyrogen-free water, before use. Inanother aspect, the pharmaceutical composition does not comprise anadjuvant or any other substance added to enhance the immune responsestimulated by the peptide. In another aspect, the pharmaceuticalcomposition comprises a substance that inhibits an immune response tothe peptide. Methods of formulation are known in the art, for example,as disclosed in Remington's Pharmaceutical Sciences, latest edition,Mack Publishing Co., Easton P.

In addition to the formulations described previously, the agents canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation or transcutaneous delivery (forexample subcutaneously or intramuscularly), intramuscular injection oruse of a transdermal patch. Thus, for example, the agents can beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

In another aspect, pharmaceutical compositions comprising one or moreagents of the present invention exert local and regional effects whenadministered topically or injected at or near particular sites ofinfection. Direct topical application, e.g., of a viscous liquid,solution, suspension, dimethylsulfoxide (DMSO)-based solutions,liposomal formulations, gel, jelly, cream, lotion, ointment,suppository, foam, or aerosol spray, can be used for localadministration, to produce for example local and/or regional effects.Pharmaceutically appropriate vehicles for such formulation include, forexample, lower aliphatic alcohols, polyglycols (e.g., glycerol orpolyethylene glycol), esters of fatty acids, oils, fats, silicones, andthe like. Such preparations can also include preservatives (e.g.,p-hydroxybenzoic acid esters) and/or antioxidants (e.g., ascorbic acidand tocopherol). See also Dermatological Formulations: Percutaneousabsorption, Barry (Ed.), Marcel Dekker Incl, 1983. In another aspect,local/topical formulations comprising a fatty acid synthesis pathwayinhibitor e.g., an inhibitor of FASN gene expression or FASN proteinactivity, are used to treat epidermal or mucosal viral infections.

Pharmaceutical compositions of the present invention can contain acosmetically or dermatologically acceptable carrier. Such carriers arecompatible with skin, nails, mucous membranes, tissues and/or hair, andcan include any conventionally used cosmetic or dermatological carriermeeting these requirements. Such carriers can be readily selected by oneof ordinary skill in the art. In formulating skin ointments, an agent orcombination of agents of the instant invention can be formulated in anoleaginous hydrocarbon base, an anhydrous absorption base, awater-in-oil absorption base, an oil-in-water water-removable baseand/or a water-soluble base. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Ointments and creams can, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and willin general also containing one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

The compositions according to the present invention can be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (O/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Otherthan the agents of the invention, the amounts of the variousconstituents of the compositions according to the invention are thoseconventionally used in the art. These compositions in particularconstitute protection, treatment or care creams, milks, lotions, gels orfoams for the face, for the hands, for the body and/or for the mucousmembranes, or for cleansing the skin. The compositions can also consistof solid preparations constituting soaps or cleansing bars.

Compositions of the present invention can also contain adjuvants commonto the cosmetic and dermatological fields, such as hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,sunscreens, odor-absorbers and dyestuffs. The amounts of these variousadjuvants are those conventionally used in the fields considered and,for example, are from about 0.01% to about 20% of the total weight ofthe composition. Depending on their nature, these adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid vesicles.

In another aspect, ocular viral infections can be effectively treatedwith ophthalmic solutions, suspensions, ointments or inserts comprisingan agent or combination of agents of the present invention. Eye dropscan be prepared by dissolving the active ingredient in a sterile aqueoussolution such as physiological saline, buffering solution, etc., or bycombining powder compositions to be dissolved before use. Other vehiclescan be chosen, as is known in the art, including but not limited to:balance salt solution, saline solution, water soluble polyethers such aspolyethyene glycol, polyvinyls, such as polyvinyl alcohol and povidone,cellulose derivatives such as methylcellulose and hydroxypropylmethylcellulose, petroleum derivatives such as mineral oil and whitepetrolatum, animal fats such as lanolin, polymers of acrylic acid suchas carboxypolymethylene gel, vegetable fats such as peanut oil andpolysaccharides such as dextrans, and glycosaminoglycans such as sodiumhyaluronate. If desired, additives ordinarily used in the eye drops canbe added. Such additives include isotonizing agents (e.g., sodiumchloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g.,benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.;e.g., hyaluronic acid or its salt such as sodium hyaluronate, potassiumhyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate,etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinkedpolyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,carboxymethyl cellulose, hydroxy propyl cellulose or other agents knownto those skilled in the art).

The solubility of the components of the present compositions can beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known tothose skilled in the art. Such co-solvents can be employed at a level offrom about 0.01% to 2% by weight.

The compositions of the invention can be packaged in multidose form.Preservatives can be preferred to prevent microbial contamination duringuse. Suitable preservatives include: benzalkonium chloride, thimerosal,chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,edetate disodium, sorbic acid, Onamer M, or other agents known to thoseskilled in the art. In the prior art ophthalmic products, suchpreservatives can be employed at a level of from 0.004% to 0.02%. In thecompositions of the present application the preservative, preferablybenzalkonium chloride, can be employed at a level of from 0.001% to lessthan 0.01%, e.g. from 0.001% to 0.008%, preferably about 0.005% byweight. It has been found that a concentration of benzalkonium chlorideof 0.005% can be sufficient to preserve the compositions of the presentinvention from microbial attack.

In another aspect, viral infections of the ear can be effectivelytreated with otic solutions, suspensions, ointments or insertscomprising an agent or combination of agents of the present invention.

In another aspect, the agents of the present invention are delivered insoluble rather than suspension form, which allows for more rapid andquantitative absorption to the sites of action. In general, formulationssuch as jellies, creams, lotions, suppositories and ointments canprovide an area with more extended exposure to the agents of the presentinvention, while formulations in solution, e.g., sprays, provide moreimmediate, short-term exposure.

In another aspect relating to topical/local application, thepharmaceutical compositions can include one or more penetrationenhancers. For example, the formulations can comprise suitable solid orgel phase carriers or excipients that increase penetration or helpdelivery of agents or combinations of agents of the invention across apermeability barrier, e.g., the skin. Many of thesepenetration-enhancing compounds are known in the art of topicalformulation, and include, e.g., water, alcohols (e.g., terpenes likemethanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide,decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g.,2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),laurocapram, acetone, dimethylacetamide, dimethylformamide,tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic,amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodiumlauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines,amides, clofibric acid amides, hexamethylene lauramide, proteolyticenzymes, α-bisabolol, d-limonene, urea and N,N-diethyl-m-toluamide, andthe like. Additional examples include humectants (e.g., urea), glycols(e.g., propylene glycol and polyethylene glycol), glycerol monolaurate,alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and/or otherpolymers. In another aspect, the pharmaceutical compositions willinclude one or more such penetration enhancers.

In another aspect, the pharmaceutical compositions for local/topicalapplication can include one or more antimicrobial preservatives such asquaternary ammonium compounds, organic mercurials, p-hydroxy benzoates,aromatic alcohols, chlorobutanol, and the like.

Gastrointestinal viral infections can be effectively treated withorally- or rectally delivered solutions, suspensions, ointments, enemasand/or suppositories comprising an agent or combination of agents of thepresent invention.

Respiratory viral infections can be effectively treated with aerosolsolutions, suspensions or dry powders comprising an agent or combinationof agents of the present invention. Administration by inhalation isparticularly useful in treating viral infections of the lung, such as anHRV infection. The aerosol can be administered through the respiratorysystem or nasal passages. For example, one skilled in the art willrecognize that a composition of the present invention can be suspendedor dissolved in an appropriate carrier, e.g., a pharmaceuticallyacceptable propellant, and administered directly into the lungs using anasal spray or inhalant. For example, an aerosol formulation comprisinga fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN geneexpression or FASN protein activity, can be dissolved, suspended oremulsified in a propellant or a mixture of solvent and propellant, e.g.,for administration as a nasal spray or inhalant. Aerosol formulationscan contain any acceptable propellant under pressure, such as acosmetically or dermatologically or pharmaceutically acceptablepropellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat the agent or combination of agents of the present invention iscarried into the respiratory tree of the subject when administered bythe nasal or oral respiratory route. Inhalation solutions can beadministered, for example, by a nebulizer. Inhalations or insufflations,comprising finely powdered or liquid drugs, can be delivered to therespiratory system as a pharmaceutical aerosol of a solution orsuspension of the agent or combination of agents in a propellant, e.g.,to aid in disbursement. Propellants can be liquefied gases, includinghalocarbons, for example, fluorocarbons such as fluorinated chlorinatedhydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as wellas hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present invention includefluorocarbon propellants in which all hydrogens are replaced withfluorine, chlorofluorocarbon propellants in which all hydrogens arereplaced with chlorine and at least one fluorine, hydrogen-containingfluorocarbon propellants, and hydrogen-containing chlorofluorocarbonpropellants. Halocarbon propellants are described in Johnson, U.S. Pat.No. 5,376,359, issued Dec. 27, 1994; Byron et al., U.S. Pat. No.5,190,029, issued Mar. 2, 1993; and Purewal et al., U.S. Pat. No.5,776,434, issued Jul. 7, 1998. Hydrocarbon propellants useful in theinvention include, for example, propane, isobutane, n-butane, pentane,isopentane and neopentane. A blend of hydrocarbons can also be used as apropellant. Ether propellants include, for example, dimethyl ether aswell as the ethers. An aerosol formulation of the invention can alsocomprise more than one propellant. For example, the aerosol formulationcan comprise more than one propellant from the same class, such as twoor more fluorocarbons; or more than one, more than two, more than threepropellants from different classes, such as a fluorohydrocarbon and ahydrocarbon. Pharmaceutical compositions of the present invention canalso be dispensed with a compressed gas, e.g., an inert gas such ascarbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of an agent of the invention such asa fatty acid synthesis pathway inhibitor e.g., an inhibitor of FASN geneexpression or FASN protein activity, in (substantially) pure propellantor as a mixture of propellant and solvent. The solvent can be used todissolve the agent and/or retard the evaporation of the propellant.Solvents useful in the invention include, for example, water, ethanoland glycols. Any combination of suitable solvents can be use, optionallycombined with preservatives, antioxidants, and/or other aerosolcomponents.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation can comprise a suspension of an agent orcombination of agents of the instant invention, e.g., a fatty acidsynthesis pathway inhibitor, e.g., an inhibitor of FASN gene expressionor FASN protein activity, and a dispersing agent. Dispersing agentsuseful in the invention include, for example, sorbitan trioleate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants, preservatives, antioxidant,and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion aerosol formulation can include, for example, an alcohol suchas ethanol, a surfactant, water and a propellant, as well as an agent orcombination of agents of the invention, e.g., a fatty acid synthesispathway, e.g., an inhibitor of FASN gene expression or FASN proteinactivity. The surfactant used can be nonionic, anionic or cationic. Oneexample of an emulsion aerosol formulation comprises, for example,ethanol, surfactant, water and propellant. Another example of anemulsion aerosol formulation comprises, for example, vegetable oil,glyceryl monostearate and propane.

The compounds of the invention can be formulated for administration assuppositories. A low melting wax, such as a mixture of triglycerides,fatty acid glycerides, Witepsol S55 (trademark of Dynamite NobelChemical, Germany), or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the invention can be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

It is envisioned additionally, that the compounds of the invention canbe attached releasably to biocompatible polymers for use in sustainedrelease formulations on, in or attached to inserts for topical,intraocular, periocular, or systemic administration. The controlledrelease from a biocompatible polymer can be utilized with a watersoluble polymer to form a instillable formulation, as well. Thecontrolled release from a biocompatible polymer, such as for example,PLGA microspheres or nanospheres, can be utilized in a formulationsuitable for intra ocular implantation or injection for sustainedrelease administration, as well. Any suitable biodegradable andbiocompatible polymer can be used.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are present in aneffective amount, i.e., in an amount effective to achieve therapeuticand/or prophylactic benefit in a host with at least one viral infectionor in a subject having cancer. The actual amount effective for aparticular application will depend on the condition or conditions beingtreated, the condition of the subject, the formulation, and the route ofadministration, as well as other factors known to those of skill in theart. Determination of an effective amount of a fatty acid synthesispathway inhibitor e.g., an inhibitor of FASN gene expression or FASNprotein activity, is well within the capabilities of those skilled inthe art, in light of the disclosure herein, and will be determined usingroutine optimization techniques.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating, liver, topical and/or gastrointestinal concentrations thathave been found to be effective in animals. One skilled in the art candetermine the effective amount for human use, especially in light of theanimal model experimental data described herein. Based on animal data,and other types of similar data, those skilled in the art can determinethe effective amounts of compositions of the present inventionappropriate for humans.

The effective amount when referring to an agent or combination of agentsof the invention will generally mean the dose ranges, modes ofadministration, formulations, etc., that have been recommended orapproved by any of the various regulatory or advisory organizations inthe medical or pharmaceutical arts (e.g., FDA, AMA) or by themanufacturer or supplier.

Further, appropriate doses for a fatty acid synthesis pathway inhibitore.g., an inhibitor of FASN gene expression or FASN protein activity, canbe determined based on in vitro experimental results. For example, thein vitro potency of an agent in inhibiting a fatty acid synthesispathway component, e.g., FASN gene expression or FASN protein activity,provides information useful in the development of effective in vivodosages to achieve similar biological effects.

In another aspect, administration of agents of the present invention canbe intermittent, for example administration once every two days, everythree days, every five days, once a week, once or twice a month, and thelike. In another aspect, the amount, forms, and/or amounts of thedifferent forms can be varied at different times of administration.

A person of skill in the art would be able to monitor in a patient theeffect of administration of a particular agent. For example, HIV viralload levels can be determined by techniques standard in the art, such asmeasuring CD4 cell counts, and/or viral levels as detected by PCR. Othertechniques would be apparent to one of skill in the art.

Having now generally described various aspects and aspects of theinvention, the same will be more readily understood through reference tothe following examples which are provided by way of illustration, andare not intended to be limiting, unless specified.

EXAMPLES Example Synthesis of Compounds of the Present Disclosure

General:

All reactions and manipulations described were carried out in wellventilated fume-hoods. Operations and reactions carried out at elevatedor reduced pressure were carried out behind blast shields.Abbreviations: ACN, acetonitrile; AcOH, acetic acid; AIBN,azobisisobutyronitrile; BuLi, butyl lithium; CDI,1,1′-Carbonyldiimidazole; DBU, 1,8-Diazabicyclo[5.4.0]undec-7-ene; DCE,1,2-dichloroethane; DCM, dichloromethane or methylene chloride; DIEA,N,N-Diisopropylethylamine; DMAP, 4-dimethylaminopyridine; DMF,N,N-dimethylformamide; DMSO, dimethylsulfoxide; EDC,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; EtOAc,ethyl acetate; EtOH, Ethanol; HATU,2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate; HBTU,O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate or2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminiumhexafluorophosphate; HMPA, hexamethylphosphoramide; HOAc, acetic acid;HOBT, 1-Hydroxybenzotriazole; LDA, lithium diisopropylamine; MeOH,methanol; MSCI, methanesulfonyl chloride; MsOH, methanesulfonic acid;NBS, N-bromosuccinimide; NIS, N-iodosuccinimide; PE, petroleum ether;PTAT, phenyltrimethylammonium tribromide; PTSA, p-toluenesulfonic acid;Py, pyridine; Pyr, pyridine; TEA, triethylamine; TFA, trifluoroaceticacid; THF, tetrahydrofuran; TMSCl, chlorotrimethylsilane; TsOH,p-toluenesulfonic acid.

Compound 1.1. tert-Butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

To a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331.21 mmol,1.10 equiv) in tetrahydrofuran (800 mL) under nitrogen at −78° C. wasadded dropwise of a solution of butyllithium (150 mL, 2.43 M in THF,1.05 equiv) during 30 min. The resulting solution was stirred for 2 h at−78° C. To this was then added a solution of tert-butyl4-oxopiperidine-1-carboxylate (60 g, 301.13 mmol, 1.00 equiv) intetrahydrofuran (800 mL) dropwise with stirring at −78° C. during 30min. After stirring for 1 h at −78° C., reaction was carefully quenchedwith 350 mL of H₂O. The resulting mixture was extracted with 2×400 mL ofethyl acetate and the combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:200-1:10) as eluent to yield 91 g (85%) of the title compound as ayellow oil.

Compound 1.2. tert-Butyl4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate

A solution of tert-butyl4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.1, 36 g,101.05 mmol, 1.00 equiv), Pd(PPh₃)₄ (11.7 g, 10.12 mmol, 0.05 equiv),and Zn(CN)₂ (17.9 g, 152.44 mmol, 1.51 equiv) in DMF (400 mL) undernitrogen was stirred overnight at 80° C. After reaching ambienttemperature, the reaction was then quenched by the addition of 600 mL ofFeSO₄ (aq., sat.) and diluted with ethyl acetate. The resulting mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water, and ethyl acetate. The layers were separated and theaqueous phase was extracted with 2×300 mL of ethyl acetate. The combinedorganic layers were washed with 1×200 mL of potassium carbonate (aq.,sat.) followed by 1×200 mL of brine, dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:200-1:5) as eluentto yield 23 g (75%) of the title compound as a white solid.

Compound 1.3. tert-Butyl4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Into a round-bottom flask, was placed a solution of tert-butyl4-(4-cyanophenyl)-4-hydroxypiperidine-1-carboxylate (compound 1.2, 2 g,6.61 mmol, 1.00 equiv) in pyridine (40 mL). POCl₃ (10.16 g, 66.26 mmol,10.02 equiv) was carefully added. The resulting mixture was stirredunder nitrogen overnight at room temperature and then concentrated undervacuum. The residue was taken up in 20 mL of DCM, washed with 2×20 mL ofsodium bicarbonate (aq), dried (Na₂SO₄), and concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with PE/EtOAc (100:1-30:1) as eluent to yield 1.4 g (74%)of the title compound as a white solid.

Compound 1.4. tert-Butyl 4-(4-cyanophenyl)piperidine-1-carboxylate

Around-bottom flask, containing a solution of tert-butyl4-(4-cyanophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (compound 1.3,500 mg, 1.76 mmol, 1.00 equiv) in ethyl acetate (20 mL) was purged withnitrogen gas. To the solution was then added palladium on carbon (0.1 g,10%, 60% water) and the flask was then further purged with nitrogen. Theatmosphere was then changed to hydrogen and the mixture was stirredovernight at room temperature. After purging the system with nitrogen,the solids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield 0.2 g (40%) of the title compound as ayellow oil.

Compound 1.5. 4-(Piperidin-4-yl)benzonitrile hydrochloride

Into a 100-mL 3-necked round-bottom flask, was placed a solution oftert-butyl 4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 4 g,13.99 mmol, 1.00 equiv) in ethyl acetate (60 mL). Hydrogen chloride(gas) was bubbled through the solution and the resulting mixture wasstirred for 1 h at room temperature. The formed precipitate wascollected by filtration and dried to yield 2.2 g (71%) of the titlecompound as a white solid. m/z (ES+) 187 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.72 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 3.54 (d withfine structure, J=12.6 Hz, 2H), 3.18 (t with fine structure, J=12.2 Hz,2H), 3.12-1.97 (m, 1H), 2.11 (d with fine structure, J=14.1 Hz, 2H),2.04-1.84 (m, 2H).

Compound 1.6. Methyl 3-bromo-4-methylbenzoate

A solution of 3-bromo-4-methylbenzoic acid (20 g, 93.00 mmol, 1.00equiv) and sulfuric acid (20 mL) in methanol (100 mL) was stiffedovernight at 80° C. The mixture was then concentrated under reducedpressure and the residue was diluted with 500 mL of ethyl acetate. Theresulting mixture was washed with 3×200 mL of water, 1×200 mL of sodiumbicarbonate (aq), followed by 1×200 mL of brine. The organic phase wasdried over anhydrous sodium sulfate, concentrated under reducedpressure, and dried to yield 20 g (94%) of the title compound as a darkred oil.

Compound 1.7. Methyl 3-cyano-4-methylbenzoate

A mixture of methyl 3-bromo-4-methylbenzoate (compound 1.6, 18 g, 78.58mmol, 1.00 equiv), Zn(CN)₂ (11.1 g, 94.87 mmol, 1.20 equiv), andPd(PPh₃)₄ (7.3 g, 6.32 mmol, 0.08 equiv) in N,N-dimethylformamide (250mL) was stirred under a nitrogen atmosphere at 100° C. overnight. Aftercooling to room temperature, the reaction was then quenched by carefuladdition of 200 mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate.The resulting mixture was stirred vigorously then filtered throughcelite and washed with 1 M FeSO₄, water, and ethyl acetate. The layerswere separated and the aqueous phase was extracted with 2×500 mL ofethyl acetate. The combined organic layers were washed with 3×200 mL ofbrine, dried over (Na₂SO₄), and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:50) as eluent to yield 11 g (76%) of thetitle compound as an off-white solid.

Compound 1.8. Methyl 3-(N′-hydroxycarbamimidoyl)-4-methylbenzoate

A mixture of methyl 3-cyano-4-methylbenzoate (compound 1.7, 8 g, 43.38mmol, 1.00 equiv, 95%), NH₂OH.HCl (3.785 g, 54.86 mmol, 1.20 equiv), andN,N-Diisopropylethylamine (DIEA, 17.7 g, 136.95 mmol, 3.00 equiv) intetrahydrofuran (100 mL) was stirred overnight at 70° C. After coolingto room temperature, the mixture was concentrated under reducedpressure. The residue was taken up in water and the pH was adjusted to2-3 with hydrogen chloride (aqueous, 1 M). After washing the mixturewith 3×40 mL of ethyl acetate, the pH of the aqueous layer was adjustedto 8-9 with NaOH (aqueous, 2 M) followed by extraction with 3×30 mL ofethyl acetate. The combined organic layers were dried over (Na₂SO₄) andconcentrated under reduced pressure to yield 2.76 g (29%) of the titlecompound as a white solid.

Compound 1.9. Methyl 3-carbamimidoyl-4-methylbenzoate

A round-bottom flask, containing a solution of methyl3-(N′-hydroxycarbamimidoyl)-4-methylbenzoate (compound 1.8, 8 g, 36.50mmol, 1.00 equiv, 95%) in methanol (150 mL) was purged with nitrogengas. To the solution was added palladium on carbon (9 g, 10%, 60% water)and the flask was then further purged with nitrogen gas. The atmospherewas then changed to hydrogen and the mixture was stirred overnight at25° C. under a balloon. After purging the system with nitrogen, thesolids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield 4 g (54%) of the title compound as abrown solid.

Compound 1.10.1 3-Bromodihydro-2H-pyran-4(3H)-one

To a mixture of dihydro-2H-pyran-4(3H)-one (10 g, 99.88 mmol, 1.00equiv) and NH₄OAc (3.56 g, 46.23 mmol) in tetrahydrofuran (100 mL) at 0°C. under nitrogen was added in several batches N-bromosuccinimide (17.8g, 100.00 mmol, 1.00 equiv). The resulting mixture was stiffed overnightat 30° C. under nitrogen. The reaction mixture was then filtered and thefiltrate was concentrated. The residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1/10-1/5) aseluent to yield 15 g (50%) of the title compound as a brown oil.

Compound 1.10. Methyl4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate

A mixture of methyl 3-carbamimidoyl-4-methylbenzoate (compound 1.9, 400mg, 1.98 mmol, 1.00 equiv, 95%), 3-bromodihydro-2H-pyran-4(3H)-one(compound 1.10.1, 750 mg, 2.09 mmol, 1.00 equiv), and potassiumcarbonate (580 mg, 4.20 mmol, 2.00 equiv) in CH₃CN (15 mL) was stirredovernight at 80° C. under nitrogen. After cooling to ambienttemperature, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in 50 mL of ethyl acetate and washedwith 2×10 mL of H₂O. The organic phase was dried over (Na₂SO₄) andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography and purified using ethylacetate/petroleum ether (1/3) to yield 0.21 g (37%) of the titlecompound as a white solid.

Compound 1.11.4-Methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid

A mixture of methyl4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate(compound 1.10, 210 mg, 0.73 mmol, 1.00 equiv, 95%) and sodium hydroxide(92.65 mg, 2.32 mmol, 3.00 equiv) in 12 mL methanol/H₂O (2:1) wasstirred for at 60° C. in an oil bath. After 2 h, the reaction mixturewas concentrated under reduced pressure and the residue was taken up in5 mL of H₂O. The resulting mixture was washed with 3×10 mL of ethylacetate and the pH of the aqueous layer was then adjusted to 2-3 usinghydrogen chloride (aq., 2 M). The resulting mixture was extracted with3×30 mL of ethyl acetate. The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to yield 0.21 g (89%)of the title compound as a white solid.

Compound 1. Methyl4-(1-(4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

A mixture of4-methyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoic acid(compound 1.11, 60 mg, 0.22 mmol, 1.00 equiv, 95%), EDCI (88.4 mg, 0.46mmol, 2.00 equiv), DMAP (85.12 mg, 0.70 mmol, 3.00 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 52 mg, 0.23mmol, 1.00 equiv) in DMF was stirred at room temperature. After 3 h, thereaction mixture was diluted with 40 mL of DCM and washed with 2×10 mLof NH₄Cl (aq.sat.) followed by 2×10 mL of brine. The organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The crudeproduct (˜100 mg) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150mm Sum; mobile phase, WATER WITH 0.05% TFA and CH3CN (15.0% CH3CN up to42.0% in 12 min, up to 100.0% in 1 min); Detector, uv 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 32.9 mg (34%) of the title compound as a white solid. m/z (ES+)427 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.73-7.65 (m, 4H), 7.61 (d, J=5.7Hz, 1H), 7.50 (d, J=6.0 Hz, 2H), 4.89-4.78 (1H partially obscured bywater peak), 4.81 (s, 2H), 4.10 (t, J=4.1 Hz, 2H), 3.94-3.81 (m, 1H),−3.35 (1H partially obscured by methanol solvent peak), 3.08-1.95 (m,2H), 2.92 (t, J=4.1 Hz, 2H), 2.52 (s, 3H), 2.08-1.92 (m, 1H), 1.92-1.65(m, 3H). ¹H NMR (400 MHz, CDCl₃): δ 7.63 (d, J=8.3 Hz, 2H), 7.34 (d,J=8.3 Hz, 2H), 7.30 (s, 1H) 7.50 (m, 2H), 4.89 (d, J=13.0 Hz, 1H), 4.81(s, 2H), 4.05 (t, J=5.2 Hz, 2H), 3.77 (d, J=13.2 Hz, 1H), 3.30 (t,J=13.0 Hz, 1H), 3.01-2.84 (m, 4H), 2.34 (s, 3H), 2.06 (d, J=13.7 Hz,1H), 1.86 (d, J=12.9 Hz, 1H), 1.76 (q, J=12.8 Hz, 1H), 1.57 (q, J=11.7Hz, 1H).

Compound 2.1. 5-Iodo-2,4-dimethylbenzoic acid

A solution of 2,4-dimethylbenzoic acid (20 g, 133.18 mmol, 1.00 equiv),sodium periodate (14.27 g, 66.72 mmol, 0.50 equiv), iodine (37.25 g,146.76 mmol, 1.10 equiv), and sulfuric acid (1.96 g, 19.98 mmol, 0.15equiv) in acetic acid (150 mL) was stirred at 110° C. in an oil bath.After 6 h, the reaction mixture was allowed to reach ambient temperatureand was then diluted with 1.2 L of water. To this was carefully added800 mL of aq Na₂S₂O₃ (aq., sat.). The resulting solids were collected byfiltration, dissolved in 1.2 L of ethyl acetate, and washed with 1×300mL of Na₂S₂O₃ (aq., sat.) followed by 1×400 mL of brine. The organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure. Thecrude residue was re-crystallized from ethanol:H₂O (2:1) to yield 30 g(82%) of the title compound as a white solid.

Compound 2.2. Methyl 5-iodo-2,4-dimethylbenzoate

A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1, 10 g, 32.60mmol, 1.00 equiv, 90%) and sulfuric acid (10 mL) in methanol (100 mL)was stirred overnight at 80° C. After cooling to room temperature, themixture was concentrated under reduced pressure and the residue wasdiluted with 200 mL of ethyl acetate. The resulting mixture was washedwith 3×50 mL of water, 2×50 mL of sodium bicarbonate (aq. sat.),followed by 2×50 mL of brine. The organic phase was dried over anhydroussodium sulfate and concentrated under reduced pressure to yield 9.2 g(88%) of the title compound as a yellow oil.

Compound 2.3. Methyl 5-cyano-2,4-dimethylbenzoate

A solution of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2, 9.2 g,31.71 mmol, 1.00 equiv), Zn(CN)₂ (4.46 g, 38.12 mmol, 1.20 equiv), andPd(PPh₃)₄ (2.93 g, 2.54 mmol, 0.08 equiv) in N,N-dimethylformamide (120mL) was stirred under a nitrogen atmosphere at 100° C. overnight. Aftercooling to room temperature, the reaction was then quenched by carefuladdition of 100 mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate.The resulting mixture was stirred vigorously then filtered throughcelite and washed with 1 M FeSO₄, water, and ethyl acetate. The layerswere separated and the aqueous phase was extracted with 2×100 mL ofethyl acetate. The combined organic layers were washed with 2×20 mL ofbrine, dried (Na₂SO₄), and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:5) as eluent to yield 6.2 g (93%) of thetitle compound as a white solid.

Compound 2.4. Methyl 5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate.

A solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 6 g,28.54 mmol, 1.00 equiv, 90%) and NH₂OH (10 mL, 5.00 equiv, 50% in water)in EtOH (20 mL) was stirred at 100° C. in an oil bath. After 2 h, themixture was cooled to room temperature and concentrated under reducedpressure. The residue was diluted with 100 mL of ethyl acetate, washedwith 2×20 mL of brine, dried (Na₂SO₄), and concentrated under reducedpressure to yield 4.66 g (66%) of the title compound as a white solid.

Compound 2.5. Methyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride

A solution of methyl 5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate

(compound 2.4, 4.66 g, 18.87 mmol, 1.00 equiv, 90%) and Ac₂O (2.36 g,23.09 mmol, 1.10 equiv) in AcOH (21 mL) was stirred at room temperature.After 5 minutes, the flask was purged with nitrogen and HCOOK (8.8 g,104.76 mmol, 5.00 equiv) and palladium on carbon (10%, 2.33 g) wereadded. The flask was purged with nitrogen followed by hydrogen. Themixture was stirred under a hydrogen atmosphere (balloon) at roomtemperature for 4 h. After purging the system with nitrogen, the solidswere removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was dissolved in 50 mL of ethanol and thepH was adjusted to 5-6 with hydrogen chloride (aq., 5 M). The resultingsolids were removed by filtration and the filtrate was concentratedunder reduced pressure to yield 4 g of the title compound as a whitesolid.

Compound 2.6. tert-Butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A mixture of methyl methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 500 mg, 90%), tert-butyl3-bromo-4-oxopiperidine-1-carboxylate (860 mg, 2.78 mmol), and potassiumcarbonate (570 mg, 4.12 mmol) in CH₃CN (15 mL) was stiffed overnightunder nitrogen at 80° C. After cooling to ambient temperature, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in 25 mL of ethyl acetate and washed with 2×10 mL of H₂O.The organic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude product thus obtained was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:3) as eluentto yield 0.3 g of the title compound as a white solid.

Compound 2.7.5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid

A mixture of tert-butyl2-(5-(methoxycarbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 2.6, 300 mg, 0.70 mmol, 1.00 equiv, 90%) and sodium hydroxide(62 mg, 1.55 mmol, 2.00 equiv) in 15 mL methanol/H₂O (2:1) was stiffedfor at 40° C. in an oil bath. After 2 h, the reaction mixture wasconcentrated to about 1/3 of the volume under reduced pressure. The pHvalue of the remaining mixture was adjusted to 3-4 with hydrogenchloride (aq., 1 M). The resulting solids were collected by filtrationand dried in an oven under reduced pressure to yield 0.2 g (69%) of thetitle compound as a yellow solid.

Compound 2.8. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

A solution of compound 2.7 (125 mg, 0.30 mmol, 1.00 equiv, 90%), DIEA(130.5 mg, 1.01 mmol, 3.00 equiv), HBTU (256.2 mg, 0.68 mmol, 2.00equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,75 mg, 0.30 mmol, 1.00 equiv) in DMF (5 mL) was stirred overnight atroom temperature. The reaction mixture was then diluted with 50 mL ofethyl acetate, washed with 2×20 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography and purified using ethylacetate/petroleum ether (1:1) to yield 0.1 g (55%) of the title compoundas a yellow solid.

Compound 2.9.4-(1-(2,4-Dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution of tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 2.8, 100 mg, 0.17 mmol, 1.00 equiv, 90%) in dichloromethane (3mL) was added trifluoroacetic acid (1 mL). The resulting mixture wasstirred at room temperature. After 2 h, the reaction mixture wasconcentrated under reduced pressure. The residue was taken up indichloromethane and washed with sodium bicarbonate (aq., sat.). Theorganic phase was dried (Na₂SO₄) and concentrated under reduced pressureto yield 0.1 g (68%) of the title compound as a yellow solid.

Compound 2.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

To a stirred mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 20 mg, 0.02 mmol, 1.00 equiv, 50%) in DMF (2 mL) undernitrogen was added a solution of Ac₂O (2.4 mg, 0.02 mmol, 1.00 equiv) inDMF (0.2 mL) dropwise at 0° C. The resulting solution was stirred for 1h at 0-3° C. in a water/ice bath. The reaction mixture was then dilutedwith 50 mL of ethyl acetate and washed with 2×20 mL of brine. Theorganic phase was dried (Na₂SO₄) and concentrated under reducedpressure. The crude residue (50 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-006(Waters)): Column, abridge C18;mobile phase, WATER WITH 0.05% NH₃.H₂O and CH₃CN (hold 5% CH₃CN in 2min, up to 20%-46% in 10 min, up to 100% in 12 min, down to 20% in 14min); Detector, UV 254/220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 5.5 mg of the title compound as awhite solid. m/z (ES+) 482 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d,J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.39-7.28 (m, 2H), 4.90 (m, 1H,partially obscured by the solvent peak), 4.67 and 4.62 (2 singlets,acetamide rotamers, MeCONCH₂-imidazole, 2H), 3.92 (m, 2H), 3.66 (m, 1H),3.23 (m, 1H), 3.00 (m, 2H), 2.85-2.76 (m, 2H), 2.48 (s, 3H), 2.41 and2.31 (2 singlets, aryl amide rotamers, ArCH₃, 3H), 2.25 and 2.22 (2singlets, acetamide rotamers, CH₃CON, 3H), 2.04 (m, 1H), 1.92-1.20 (m,3H).

Compound 3.4-(1-(3-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 468 (M+H)⁺.

Compound 4.4-(1-(4-Methyl-3-(5-(methylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 504 (M+H)⁺.

Compound 5.4-(1-(5-(5-(Isopropylsulfonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 546 (M+H)⁺.

Compound 6.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)-2-fluorobenzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 459 (M+H)⁺.

Compound 7.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-sulfonamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 547 (M+H)⁺.

Compound 8.(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 484 (M+H)⁺.

Compound 9.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4,5,6,7-tetrahydro-1H-benzo[d]imidazole-6-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 496 (M+H)⁺.

Compound 11.1. tert-Butyl4-(4-cyanophenyl)-4-fluoropiperidine-1-carboxylate

To a stirred solution of compound 1.2 (5 g, 16.54 mmol, 1.00 equiv) indichloromethane (250 mL) under nitrogen at −78° C. was added dropwiseDeoxo-Fluor® (4.4 g, 19.89 mmol, 1.20 equiv). The resulting mixture wasstirred for 1 h at −78° C. The reaction mixture was then carefullyquenched by the addition of 50 mL of sodium bicarbonate (aq.sat.) andextracted with 3×100 mL of dichloromethane. The combined organic layerswere washed with 150 mL of brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:30) as eluent to yield 2.5 g (35%) of thetitle compound as a white solid.

Compound 11.2. 4-(4-Fluoropiperidin-4-yl)benzonitrile

To a stirred solution of compound 11.1 (620 mg, 1.02 mmol, 1.00 equiv,50%) in DCM (40 mL) was added dropwise trifluoroacetic acid (6 g, 52.62mmol, 51.66 equiv). After stirring at ambient temperature for 2 h, themixture was concentrated under reduced pressure. The residue was takenup in DCM and treated with aqueous sodium bicarbonate. The phases wereseparated and the aqueous layer was extracted with 2×50 mL DCM. Thecombined organic layers were dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to yield 0.4 g of the title compoundas a light yellow solid. m/z (ES+) 205 (M+H)⁺.

Compound 11.2HCl salt. 4-(4-Fluoropiperidin-4-yl)benzonitrilehydrochloride

The title compound was prepared using standard chemical manipulationsand a procedure similar to that used for the preparation of compound 1.5and using compound 11.1 in place of compound 1.4. m/z (ES+) 205 (M+H)⁺.¹H NMR (300 MHz, CD₃OD): δ 7.83 (d, J=6.3 Hz, 2H), 7.68 (d, J=6.3 Hz,2H), 3.55-3.32 (m, 4H), 2.58-2.40 (m, 2H), 2.28-2.22 (m, 2H).

Compound 11.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 and using compound 11.2 in place of compound 1.5. m/z (ES+) 459(M+H)⁺.

Compound 12.(4-(4-Chlorophenyl)piperidin-1-yl)(2,4-dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 450 (M+H)⁺.

Compound 13.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 482 (M+H)⁺.

Compound 14.4-(1-(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 441 (M+H)⁺.

Compound 15.(2,4-Dimethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)phenyl)(4-(4-(trifluoromethoxy)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2. m/z (ES+) 500 (M+H)⁺.

Compound 16.1. N²-(2-Methoxyethyl)-N²-methyl-5-nitropyridine-2,4-diamine

A solution of 2-chloro-5-nitropyridin-4-amine (500 mg, 2.88 mmol, 1.00equiv), triethylamine (1.167 g, 11.53 mmol, 4.00 equiv), and(2-methoxyethyl)(methyl)amine (514 mg, 5.77 mmol, 2.00 equiv) in DMF (20mL) was stiffed in a sealed tube at 55° C. behind a blast shieldovernight. After cooling to room temperature, the mixture was dilutedwith 100 mL of water and extracted with 3×150 mL of ethyl acetate. Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield 723 mg (crude) of the title compound as a darkred oil.

Compound 16.2. N²-(2-Methoxyethyl)-N²-methylpyridine-2,4,5-triamine.

Around-bottom flask, containing a solution of compound 16.1 (400 mg,1.77 mmol, 1.00 equiv)) in methanol (30 mL) was purged with nitrogengas. To the solution was then added palladium on carbon (40 mg, 10%, 60%water). The flask was purged further with nitrogen and the atmospherewas then changed to hydrogen. The mixture was stirred at roomtemperature under a balloon with hydrogen for 4 h. After purging thesystem with nitrogen, the solids were removed by filtration and thefiltrate was concentrated under reduced pressure to yield 300 mg (86%)of the title compound as a light brown solid. The crude product wasfound to be unstable and used immediately.

Compound 16.3. 5-Formyl-2,4-dimethylbenzoic acid

To a stirred solution of 5-iodo-2,4-dimethylbenzoic acid (compound 2.1,5 g, 18.11 mmol, 1.00 equiv) in tetrahydrofuran (150 mL) under nitrogenat −78° C. was added n-BuLi (2.5 M in THF, 18 mL, 2.50 equiv) dropwise.After stirring at −78° C. for 1 h, DMF (5 g, 68.4 mmol, 3.80 equiv) wasadded dropwise. The resulting mixture was stirred at −78° C. for anadditional 0.5 h and then carefully quenched by slow addition of 50 mLof water. The pH was then adjusted to ˜3-4 using aqueous HCl (aq., 6 M).The mixture was extracted with 3×200 mL of ethyl acetate. The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure. The residue thus obtained was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10-1:5) as gradientto yield 2.4 g (74%) of the title compound as a white solid.

Compound 16.4.4-(1-(5-Formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

To a stirred solution of 5-formyl-2,4-dimethylbenzoic acid (compound16.3, 950 mg, 5.33 mmol, 1.10 equiv) in DMF (15 mL) was added DIEA (2.48g, 19.19 mmol, 4.00 equiv) followed by HBTU (3.67 g, 9.68 mmol, 2.00equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,1.07 g, 4.80 mmol, 1.00 equiv). After stirring overnight at ambienttemperature, the reaction was quenched by the addition of 60 mL ofwater. The resulting mixture was extracted with 3×150 mL of ethylacetate and the organic layers were combined, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:10-1:3) as eluent to yield 1.4 g (84%) of thetitle compound as a brown oil.

Compound 16.4-(1-(5-(6-((2-Methoxyethyl)(methyl)amino)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

A solution of compound 16.2 (300 mg, 1.53 mmol, 1.30 equiv), compound16.4 (407 mg, 1.17 mmol, 1.00 equiv), and ammonium acetate (362 mg, 4.70mmol, 4.00 equiv) in ethanol (20 mL) was stirred overnight at 70° C. inan oil bath. The resulting mixture was then concentrated under vacuumand the residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:10-2:1) as eluent to yield ˜200 mg ofproduct which was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (hold 5.0% CH3CNin 2 min, up to 25.0% in 1 min, up to 55.0% in 12 min, up to 100.0% in 1min); Detector, UV 254/220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 150 mg (24%) of the titlecompound as a white solid. m/z (ES+) 523 (M+H)⁺. ¹H NMR (300 MHz,CDCl₃): δ 8.57-8.38 (m, 1H), 7.78-7.53 (m, 4H), 7.34 (d, J=7.5 Hz, 2H),7.28-7.12 (m, 2H), 5.06-4.88 (m, 1H), 3.71 (app s, 5H), 3.50 (s, 3H),3.41-3.05 (m, 4H), 3.01-2.75 (m, 2H), 2.68 (s, 3H), 2.42 & 2.31 (2singlets, amide rotamers, ArCH₃, 3H), 2.12-1.93 (m, 1H), 1.93-1.39 (m,3H).

Compound 17.4-(1-(2,4-Dimethyl-5-(6-morpholino-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 521 (M+H)⁺.

Compound 18.4-(1-(2,4-Dimethyl-5-(6-(4-methylpiperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 534 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆): 8.73 (s, 1H), 7.76 (d,J=7.5 Hz, 2H), 7.66 & 7.56 (2 singlets, amide rotamers, Ar—H, 1H), 7.49(d, J=8.1 Hz, 2H), 7.37 (s, 1H), 7.12 (s, 1H), 4.81-4.67 (m, 1H), 4.30(br s, 2H), 3.70-3.37 (m, 3H), 3.37-3.05 (m, 5H), 3.05-1.80 (m, 5H),2.60 (s, 3H), 2.37 & 2.27 (2 singlets, amide rotamers, Ar—CH₃, 3H),2.02-1.87 (m, 1H), 1.87-2.40 (m, 3H).

Compound 19.4-(1-(2,4-Dimethyl-5-(6-(piperazin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 519 (M+H)⁺.

Compound 20.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridin-4-amine

A 500 mL round bottom flask equipped with a reflux condenser was chargedwith 2-chloro-5-nitropyridin-4-amine (2.00 g, 11.5 mmol, 1.0 equiv),pyrrolidine (2.86 mL, 34.6 mmol, 3.0 equiv), potassium carbonate (4.78g, 34.6 mmol, 3.0 equiv) and acetonitrile (50 mL). The mixture washeated at 70° C. overnight under nitrogen then cooled to roomtemperature. The yellow solids were collected by filtration and washedwith acetonitrile, water and hexanes. The solids were dried to obtainthe title compound as a bright yellow solid (1.43 g, 1^(st) crop). Thesolvents from the filtrate were removed and the aqueous was extractedwith ethyl acetate. The organic extracts was dried (Na₂SO₄), filteredand removed in vacuo to obtain additional product as an orange/yellowsolid (820 mg, 2^(nd) crop). The 2^(nd) crop of product was trituratedwith ethyl acetate (3 mL) and then filtered and washed with ethylacetate (2×1 mL) and diethyl ether (3 mL) to obtain a bright yellowsolid (751 mg). The total yield of5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine obtained was 2.18 g (91%).m/z (ES+) 209.1 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 8.79 (s, 1H), 7.39(br s, 2H), 5.63 (s, 1H), 3.40 (br s, 4H), 1.93 (br s, 4H).

Compound 20.2. 6-(Pyrrolidin-1-yl)pyridine-3,4-diamine

To a 100 mL round bottom flask was added5-nitro-2-(pyrrolidin-1-yl)pyridin-4-amine (compound 20.1, 800 mg, 3.84mmol, 1.0 equiv) and Pd on carbon (10 wt % Pd, 400 mg, 0.38 mmol, 0.1equiv). The system was purged with nitrogen and charged with methanol(19 mL) followed by hydrogen. The mixture was stirred at roomtemperature under hydrogen for 4 hours then purged with nitrogen. Themixture was filtered though celite and washed extensively with MeOH. Thesolvents were removed in vacuo to obtain the title compound as a purplesolid (641 mg, 94%). m/z (ES+) 179.3 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆):δ 7.27 (s, 1H), 5.62 (s, 1H), 5.14 (br s, 2H), 3.67 (br s, 2H),3.23-3.13 (m, 4H), 1.91-1.79 (m, 4H).

Compound 20.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a 100 mL round bottom flask was added6-(pyrrolidin-1-yl)pyridine-3,4-diamine (compound 20.2, 641 mg, 3.60mmol, 1.0 equiv),4-(1-(5-formyl-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile (compound16.4, 1.25 g, 3.60 mmol, 1.0 equiv), sodium metabisulfite (890 mg, 4.68mmol, 1.3 equiv) and DMF (36 mL). The mixture was heated at 100° C.under air for 22 hours then allowed to cool to room temperature. Water(80 mL) was added slowly to the stirred solution until no furtherproduct precipitated. The solids were filtered and washed with water(2×15 mL) and dried to a brown solid (1.42 g). Additional productprecipitated from the filtrate upon standing which was filtered andwashed with water (2×10 mL) to obtain an off white solid (241 mg). Theabove reaction was repeated a second time in the exact manner andquantities as described to yield additional product (1.26 g of brownsolid upon initial precipitation, plus 288 mg of off white solid fromadditional precipitation). The aqueous filtrates from the two reactionswere combined and aqueous NaHCO₃ was added to adjust the pH to 7. Theaqueous was extracted with DCM/2% MeOH (300 mL), dried (Na₂SO₄),filtered and evaporated to obtain a brown solid (547 mg). All productsobtained were combined and purified by silica gel chromatography(DCM/MeOH) to obtain the title compound as a yellow solid (2.37 g, 65%based on the theoretical yield for the two reactions). m/z (ES+) 505.1(M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ 12.41 (br s, 1H), 8.52 (s, 1H),7.77 (d, J=8.2 Hz, 2H), 7.66 & 7.56 (2 br singlets, amide rotamers, ArH,1H), 7.49 (s, J=8.2 Hz, 2H), 7.29 (s, 1H), 6.31 (br s, 1H), 4.79-4.67(m, 1H), 3.54-3.34 (m, 5H), 3.17 (app t, J=11.8, 1H), 2.99-2.82 (m, 2H),2.63 (s, 3H), 2.33 & 2.24 (2 singlets, amide rotamers, ArCH₃, 3H),2.03-1.87 (m, 5H), 1.82-1.38 (m, 3H). Elemental analysis(C₃₁H₃₂N₆O.1.3H₂O, 528.04), found (calcd), C, 70.66 (70.51); H, 6.54(6.60); N, 15.78 (15.92).

Compound 20HCl salt.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilehydrochloride

Dichloromethane (˜50 mL) was added to4-(1-(2,4-dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 20 free base, 2.31 g, 4.58 mmol) until it completely dissolvedand then 4M HCl in dioxane (5 mL, 20 mmol, 4.3 equiv) was added. Thesolvents were removed and the residue was dissolved in DCM and removedin vacuo. The resulting hydrochloride salt was recrystallized fromboiling ethanol (180 mL) and allowed to cool to room temperature slowly.The mixture sat at room temperature overnight and then placed in thefreezer for 4 hours. The resulting solids were filtered and washed withcold ethanol (25 mL) followed by diethyl ether (25 mL). The solids weredried to obtain an off white to light grey solid (1.82 g, 73%). ¹H NMR(400 MHz, DMSO-d₆): δ 13.59 & 13.46 (2 br singlets, imidazole NHtautomers, 1H), 13.29 (br s, 1H), 8.62 (br s, 1H), 7.83 & 7.67 (2singlets, amide rotamers, ArH, 1H,), 7.78 (d, J=7.8 Hz, 2H), 7.58-7.45(m, 2H), 7.37 (s, 1H), 6.71 (br s, 1H), 4.80-4.68 (m, 1H), 3.65-3.38 (m,5H), 3.25-3.12 (m, 1H), 3.00-2.82 (m, 2H), 2.66 (s, 3H), 2.37 & 2.27 (2singlets, amide rotamers, ArCH₃, 3H), 2.13-2.01 (m, 4H), 1.98-1.87 (m,1H), 1.82-1.40 (m, 3H). Elemental analysis (C₃₁H₃₂N₆O.1.0HCl.2.4H₂O,584.32), found (calcd), C, 63.80 (63.72); H, 6.32 (6.52); N, 14.25(14.38).

Compound 20 MsOH salt.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilemethanesulfonate

4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrilehydrochloride (compound 20HCl salt, 1.82 g, 3.36 mmol) was added towater (100 mL) plus saturated NaHCO₃ (50 mL) and extracted with 1:1DCM/EtOAc (500 mL) plus MeOH (25 mL). Once the entire product completelydissolved, the layers were separated and the aqueous was extracted withadditional 1:1 DCM/EtOAc (100 mL). The combined organics was dried(Na₂SO₄), filtered and evaporated to a light yellow powder (1.68 g, 3.33mmol). The free base material was dissolved in hot acetonitrile (10 mL),then a 1.0 M aqueous methanesulfonic acid solution (3.33 mL, 3.33 mmol,1.0 equiv) was added and mixed well. Additional water (6 mL) was addedand the mixture was frozen and dried on the lyophilizer to obtain ayellow powder (1.99 g, 99%). m/z (ES+) 505.1 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 13.29 (br s, 1H), 13.10 (br s, 1H), 8.65 (br s, 1H), 7.78(d, J=8.2 Hz, 2H), 7.74 & 7.64 (2 singlets, amide rotamers, ArH, 1H,),7.50 (d, J=8.3 Hz, 2H), 7.37 (s, 1H), 6.74 (br s, 1H), 4.80-4.68 (m,1H), 3.65-3.38 (m, 5H), 3.26-3.12 (m, 1H), 3.01-2.83 (m, 2H), 2.64 (s,3H), 2.37 & 2.27 (2 singlets, amide rotamers, ArCH₃, 3H), 2.32 (s, 3H)2.12-2.00 (m, 4H), 1.98-1.88 (m, 1H), 1.82-1.39 (m, 3H). Elementalanalysis (C₃₁H₃₂N₆O.1.0MsOH.1.7H₂O, 631.36), found (calcd), C, 60.96(60.88); H, 6.14 (6.29); N, 13.21 (13.31); S: 5.08 (5.08).

Compound 21.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 491 (M+H)⁺.

Compound 22.4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 514 (M+H)⁺.

Compound 23.4-(1-(2,4-Dimethyl-5-(6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 514 (M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆+D₂O): δ 8.87 (d, J=1.8 Hz,1H), 8.52 (d, J=2.1 Hz, 1H), 7.74 (d, J=7.5 Hz, 2H), 7.66 & 7.56 (2singlets, amide rotamers, Ar—H, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.38 (br s,1H), 4.76-4.63 (m, 1H), 3.57-3.38 (m, 1H), 3.31 (s, 3H), 3.28-3.13 (m,1H), 3.03-2.85 (m, 2H), 2.60 (s, 3H), 2.35 & 2.27 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.00-1.85 (m, 1H), 1.85-1.32 (m, 3H).

Compound 24.4-(1-(5-(5-(Azetidin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 6-chloro-3-nitropyridin-2-amine and azetidine hydrochloride inplace of 2-chloro-5-nitropyridin-4-amine and(2-methoxyethyl)(methyl)amine respectively. m/z (ES+) 491 (M+H)⁺. ¹H NMR(300 MHz, CD₃OD): δ 8.06 (d, J=9.0 Hz, 1H), 7.70-7.42 (m, 6H), 6.60 (d,J=9.0 Hz, 1H), 4.90 (m, 1H, partially obscured by the solvent peak),4.32 (m, 4H), 3.65 (m, 1H), 3.03 (m, 1H), 2.62 (s, 3H), 2.57 (m, 3H),2.48 and 2.38 (2 singlets, amide rotamers, ArCH₃, 3H), 2.04 (m, 1H),1.96-1.68 (m, 4H).

Compound 25.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 andusing compound 11.2 in place of compound 1.5. m/z (ES+) 509 (M+H)⁺.

Compound 26.1. tert-Butyl4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate

To a stiffed solution of 2,5-dibromopyridine (10 g, 42.19 mmol, 1.00equiv) in toluene (1000 mL) under nitrogen at −78° C. was added dropwisen-BuLi (18 mL, 2.5 M in toluene). After 1 h at −78° C., a solution oftert-butyl 4-oxopiperidine-1-carboxylate (10 g, 50.25 mmol, 1.19 equiv)in toluene (200 mL) was added dropwise while stirring. After anadditional 2 h of stirring at −78° C., the reaction was then carefullyquenched by the addition of 300 mL of water. The resulting mixture wasextracted with 3×500 mL of ethyl acetate. The combined organic layerswere washed with 1×300 mL of brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:100-1:5) to yield 6.5 g (42%) of the title compound as a yellow oil.

Compound 26.2. tert-Butyl4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound26.1, 1 g, 2.80 mmol, 1.00 equiv), zinc cyanide (400 mg, 3.42 mmol, 1.22equiv), Pd(PPh₃)₄ (200 mg, 0.17 mmol, 0.06 equiv) in DMF (50 mL) wasstirred under nitrogen for 2 h at 100° C. After cooling to roomtemperature, the reaction was then quenched by careful addition of 300mL of FeSO₄ (aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×100 mL of ethyl acetate. Thecombined organic layers were washed with 1×100 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:4) yield 0.5 g (58%) of the titlecompound as a yellow oil.

Compound 26.3. tert-Butyl4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate

To a solution of tert-butyl4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound26.2, 1 g, 3.13 mmol, 1.00 equiv, 95%) in dichloromethane (50 mL) undernitrogen at −78° C. was added dropwise a solution ofbis(2-methoxyethyl)aminosulfur trifluoride (830 mg, 3.75 mmol, 1.20equiv) in dichloromethane (10 mL) during the course of 1 min. Theresulting mixture was stirred for 1 h at −78° C. The reaction was thencarefully quenched by dropwise addition of water and washed with 2×20 mLof sodium bicarbonate(aq) followed by 3×20 mL of brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10) to yield 0.38 g(38%) of the title compound as a white solid.

Compound 26.4. 6-(4-Fluoropiperidin-4-yl)nicotinonitriletrifluoroacetate

To a stirred solution of tert-butyl4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carboxylate (compound 26.3,1 g, 3.11 mmol, 1.00 equiv, 95%) in dichloromethane (20 mL) was addeddropwise TFA (3.75 g, 32.89 mmol, 10.57 equiv). After stirring for 1 hat 25° C., the mixture was concentrated under reduced pressure to yield0.5 g of the title compound as a brown oil.

Compound 26.6-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing compound 26.4 in place of compound 1.5. m/z (ES+) 509 (M+H)⁺.

Compound 27.4-(1-(4-Methyl-3-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 3-bromo-4-methylbenzoic acid in place of5-iodo-2,4-dimethylbenzoic acid. m/z (ES+) 491 (M+H)⁺.

Compound 28.4-(1-(3-(1H-Imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 422 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 9.35 (s, 1H), 8.60(d, J=6.6 Hz, 1H), 8.19 (d, J=6.6 Hz, 1H), 7.92 (s, 1H), 7.73-7.58 (m,4H), 7.50 (d, J=8.1 Hz, 1H), ˜4.9 (1H, partially obscured by waterpeak), 4.06-3.87 (m, 1H), 3.13-2.95 (m, 3H), 2.73 (s, 3H), 2.11-1.63 (m,4H).

Compound 29.4-(1-(3-(1H-Benzo[d]imidazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 421 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.87-7.77 (m, 3H),7.75-7.60 (m, 4H), 7.60-7.47 (m, 4H), ˜4.85 (1H, partially obscured bywater peak), 4.04-3.89 (m, 1H), 3.13-2.95 (m, 3H), 2.61 (s, 3H),2.11-1.69 (m, 4H).

Compound 30.4-(1-(3-(6-Chloro-3H-imidazo[4,5-c]pyridin-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compounds 16 and27. m/z (ES+) 456 (M+H)⁺.

Compound 31.4-(1-(2-Methyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16 butusing 5-bromo-2-methylbenzoic acid in place of5-iodo-2,4-dimethylbenzoic acid (compound 2.1). m/z (ES+) 491 (M+H)⁺. ¹HNMR (300 MHz, DMSO-d₆): δ 12.63 (br s, 1H), 8.06 (d, J=7.8 Hz, 1H), 8.01& 7.91 (2 singlets, amide rotamers, Ar—H, 1H), 7.81 (d, J=6.6 Hz, 2H),7.58-7.42 (m, 3H), 6.31 (s, 1H), 4.85 (m, 1H), 3.57-3.35 (m, 5H),3.30-3.13 (m, 1H), 3.07-1.85 (m, 2H), 2.39 & 2.29 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.89 (m, 5H), 1.87-1.40 (m, 3H).

Compound 32.4-(1-(2-Methoxy-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 507 (M+H)⁺.

Compound 33.2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 502 (M+H)⁺.

Compound 34.4-(1-(2-Chloro-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 511 (M+H)⁺.

Compound 35.4-(1-(5-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-2-(trifluoromethoxy)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 561 (M+H)⁺.

Compound 36.4-(1-(3-(6-(Pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 477 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 8.44 (s, 1H), 8.25-8.17 (m,2H), 7.77-7.63 (m, 4H), 7.51 (d, J=8.1 Hz, 2H), 6.59 (s, 1H), ˜4.85 (1H,partially obscured by water peak), 3.98-3.83 (m, 1H), 3.61-3.48 (m, 4H),˜3.4 (1H, partially obscured by methanol solvent peak), 3.12-2.96 (m,2H), 2.22-2.09 (m, 4H), 2.09-1.95 (m, 1H), 1.95 (m, 3H).

Compound 37.4-(1-(3-(6-(Isopropylamino)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 16. m/z(ES+) 465 (M+H)⁺.

Compound 38.1. Methyl tetrahydrofuran-3-carboxylate

A solution of tetrahydrofuran-3-carboxylic acid (540 mg, 4.65 mmol, 1.00equiv) and TsOH (10 mg, 0.06 mmol, 0.01 equiv) in methanol (40 mL) wasstiffed at 66° C. in an oil bath. After 16 h, the resulting mixture wascooled to room temperature and concentrated under reduced pressure. Theresidue was dissolved in 10 mL of ether, washed with 1×20 mL of NaHCO₃(aq., sat.) followed by 3×20 mL of brine, and concentrated under reducedpressure to yield 0.40 g (66%) of the title compound as a colorless oil.

Compound 38.2. Tetrahydrofuran-3-carbohydrazide

Into around-bottom flask, was placed hydrazine hydrate (20 mL). To thiswas added methyl tetrahydrofuran-3-carboxylate (compound 38.1, 390 mg,3.00 mmol, 1.00 equiv) dropwise with stirring. The resulting mixture wasstirred at 50° C. in an oil bath. After 3 h, the reaction mixture wasconcentrated and dried under reduced pressure to yield 0.29 g (74%) ofthe title compound as a colorless oil.

Compound 38.3. Methyl 3-carbamothioyl-4-methylbenzoate

A solution of methyl 3-cyano-4-methylbenzoate (compound 1.7, 880 mg,5.02 mmol, 1.00 equiv) and O,O′-diethyl dithiophosphate (1.41 g, 8.29mmol, 1.50 equiv) in THF/H₂O (40 mL) was stirred at 80° C. (CAUTION:significant gas evolution occurs—this and all other reactions describedherein should be carried out in well ventilated fume hoods). After 3 h,the organic solvent was removed under reduced pressure and the residualaqueous phase was extracted with 3×20 mL of ethyl acetate. The combinedorganic layers were concentrated under reduced pressure to yield 0.85 g(79%) of the title compound as a light yellow solid.

Compound 38.4. Methyl 3-(imino(methylthio)methyl)-4-methylbenzoate

To a stirred solution of methyl 3-carbamothioyl-4-methylbenzoate(compound 38.3, 2.10 g, 9.85 mmol, 1.00 equiv) in tetrahydrofuran (30mL) was added iodomethane (2.8 g, 19.73 mmol, 2.00 equiv) dropwise. Theresulting mixture was stirred at room temperature. After 3 h, thereaction mixture was concentrated under reduced pressure and the residuewas dried under vacuum to yield 1.6 g (73%) of the title compound as alight yellow solid.

Compound 38.5. Methyl4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoate

A solution of tetrahydrofuran-3-carbohydrazide (compound 38.2, 195 mg,1.50 mmol, 1.50 equiv) and compound 38.4 (223 mg, 1.00 mmol, 1.00 equiv)in AcOH (30 mL) was stirred at 80° C. After 4 h, the reaction mixturewas concentrated under reduced pressure and the residue was dried underhigh-vacuum to yield 153 mg (53%) of the title compound as yellow oil.

Compound 38.6.4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoic acid

To a stiffed solution of compound 38.5 (57 mg, 0.20 mmol, 1.00 equiv) inmethanol (20 mL) was added sodium hydroxide (aqueous, 1 M, 0.2 mL)dropwise. The resulting mixture was stirred at room temperature. After 4h, the organic solvent was removed under reduced pressure. The residualaqueous layer was washed with 2×20 mL of ethyl acetate. The pH of theaqueous phase was then adjusted to 4 with hydrogen chloride (aq., 1 M)and the resulting solids were collected by filtration and dried to yield23 mg (42%) of the title compound as a light yellow solid.

Compound 38.4-(1-(4-Methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

A mixture of compound 38.6 (137 mg, 0.50 mmol, 1.00 equiv), HBTU (228mg, 0.60 mmol, 1.20 equiv), DIEA (162 mg, 1.25 mmol, 2.50 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 111 mg, 0.50 mmol,1.00 equiv) in DMF (20 mL) was stirred at room temperature. After 1 h,the reaction was quenched by the addition of 20 mL of water andresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic phases were dried (Na₂SO₄) and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:100-1:3) to yield35 mg (16%) of the title compound as a brown solid. m/z (ES+) 442(M+H)⁺.

Compound 39.1. 3-Formyl-4-methylbenzoic acid

To a stirred solution of 3-bromo-4-methylbenzoic acid (2.14 g, 10.00mmol, 1.00 equiv) in tetrahydrofuran (30 mL) under nitrogen at −78° C.was added n-BuLi (10 mL, 2.5 M in THF, 2.50 equiv) dropwise. Afterstirring for 1 h below −70° C., DMF (5 mL) was slowly added. Theresulting solution was warmed slowly to room temperature and stirred for1 h. After carefully quenching the reaction by slowly adding 50 mL ofwater, the pH was adjusted to ˜3-4 using aqueous HCl (6 M). Theresulting mixture was extracted with 2×50 mL of ethyl acetate and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 1.6 g (98%) of the titlecompound as a yellow solid.

Compound 39.2.4-(1-(3-Formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile.

A mixture of 3-formyl-4-methylbenzoic acid (compound 39.1, 660 mg, 4.02mmol, 1.00 equiv), HBTU (2 g, 5.28 mmol, 1.30 equiv) inN,N-dimethylformamide (20 mL) was stiffed at room temperature. After 1h, 4-(piperidin-4-yl)benzonitrile hydrochloride (1.5, 890 mg, 4.01 mmol,1.00 equiv) and DIEA (1.03 g, 7.98 mmol, 2.00 equiv) were added. Theresulting mixture was stirred for 5 h at room temperature and thenovernight at 60° C. in. After cooling to ambient temperature, thereaction mixture was diluted with 100 mL of EtOAc and washed with 2×50mL of NH₄Cl (aq., sat.) followed by 2×50 mL of sodium bicarbonate (aq.,sat.). The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 1 g (75%) of the titlecompound as a brown oil.

Compound 39.3.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid

To a stirred mixture of4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was added dropwise asolution of KMnO₄ (1 g) in water (10 mL). The resulting mixture wasstirred overnight at 60° C. in an oil bath. After cooling to ambienttemperature, the solids were removed by filtration and the pH of thefiltrate was adjusted to ≧10 with sodium hydroxide (aqueous, 1 M). Theresulting mixture was washed with 20 mL of ethyl acetate. Aqueous 1 MHCl was then employed to adjust the pH of the aqueous layer to ˜4. Theresulting aqueous phase was extracted with 2×100 mL of ethyl acetate andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 500 mg (80%) of the titlecompound as light yellow oil.

Compound 39.4. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoate

To a stiffed mixture of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylbenzoic acid(compound 39.3, 1.392 g, 4.00 mmol, 1.00 equiv) in methanol (50 mL) wasadded sulfuric acid (784 mg, 7.99 mmol, 2.00 equiv), dropwise. Theresulting mixture was heated to reflux overnight in an oil bath. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The residue was diluted with 20 mL of EtOAc and waswashed with 1×100 mL of saturated sodium bicarbonate(aq) followed by1×100 mL of brine. The organic layer was dried (Na₂SO₄) and concentratedunder reduced pressure to yield 1.303 g (90%) of the title compound as awhite solid.

Compound 39.5.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylbenzohydrazide

A solution of compound 39.4 (1.503 g, 4.15 mmol, 1.00 equiv) andhydrazine hydrate (10 mL) in ethanol (50 mL) was heated at reflux in anoil bath. After 2 h, the mixture was concentrated under reduced pressureand the residue was dissolved in 20 mL of EtOAc. The resulting mixturewas washed with 1×50 mL of H₂O and 1×50 mL of brine. The organic layerwas dried (Na₂SO₄) and concentrated under reduced pressure to yield1.353 g (90%) of the title compound as a white solid

Compound 39.6.4-(1-(3-(5-Amino-1,3,4-oxadiazol-2-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

A mixture of compound 39.5 (380 mg, 1.05 mmol, 1.00 equiv) and sodiumbicarbonate (105.8 mg, 1.26 mmol, 1.20 equiv) in dioxane/H₂O (1:1) (50mL) was stirred at room temperature. After 5 minutes, cyanogen bromide(212 mg, 2.00 mmol, 2.00 equiv) was added. The resulting mixture wasstirred for 3 h at room temperature. The resulting solution was stirredfor 3 h at room temperature, then quenched with 30 mL of FeSO₄ (aq.,sat.) and diluted with ethyl acetate. The resulting mixture was stirredvigorously then filtered through celite and washed with 1 M FeSO₄,water, and ethyl acetate. The layers were separated and the aqueousphase was extracted with 2×50 mL of ethyl acetate. The combined organiclayers were washed with 2×50 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 397 mg (98%) of anoff-white solid.

Compound 39.4-(1-(3-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

A mixture of compound 39.6 (397 mg, 1.02 mmol, 1.00 equiv) and potassiumhydroxide (287 mg, 5.12 mmol, 5.00 equiv) in ethanol (25 mL) was heatedat reflux overnight. After cooling the reaction mixture to roomtemperature with a water bath, the pH was adjusted to ˜7 with aceticacid. The resulting mixture was concentrated under reduced pressure. Theresidue was taken up in ethyl acetate and washed with water. The organiclayer was dried (Na₂SO₄) and concentrated. The crude residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:5-1:0). The product was further purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)):Column, SunFire Prep C18, Sum, 19*150 mm; mobile phase, WATER WITH 0.05%TFA and CH₃CN (hold 5.0% CH₃CN in 2 min, up to 30.0% in 1 min, up to59.0% in 12 min, up to 100.0% in 2 min); Detector, UV 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 51.9 mg (12%) of the title compound as a white solid. m/z (ES+)416 (M+H)⁺.

Compound 40.1. tert-Butyl4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate

A solution of 4-iodobenzonitrile (510 mg, 2.22 mmol, 1.1 equiv) in THF(3 mL) was added to a 10 mL round-bottom flask and the system purgedwith nitrogen. The mixture was cooled to −40° C. then isopropylmagnesiumchloride (1.16 mL of a 2.0 M soln in THF, 2.32 mmol, 1.15 equiv) wasadded dropwise over 20 minutes. The resulting mixture was stirred at−40° C. for 2 hours then tert-butyl 4-oxoazepane-1-carboxylate (431 mg,2.02 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 15minutes. The resulting mixture was stirred at −40° C. for 1 hour thendiluted into ethyl acetate (15 mL) and washed with 0.2 M HCl (10 mL),0.1 M HCl (5 mL), saturated sodium bicarbonate (5 mL) then brine (5 mL).The organics were dried (Na₂SO₄), filtered and evaporated. To removeremaining ketone and aldol by-product, the residue was dissolved inacetonitrile (3 mL) then hydrazine (0.2 mL) was added and heated at 60°C. for 4 hours. The mixture was diluted with EtOAc (20 mL) and washedwith water (20 mL), followed by 0.5 M phosphoric acid (3×20 mL),saturated sodium bicarbonate (10 mL) and brine (10 mL). The organicswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby silica column chromatography (hexanes/ethyl acetate) to obtain thetitle compound as a pink oil which solidified upon standing (303 mg,47%). m/z (ES+) 317 (M+H)⁺.

Compound 40.2. tert-Butyl4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate andtert-butyl 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate

In a vial containing tert-butyl4-(4-cyanophenyl)-4-hydroxyazepane-1-carboxylate (compound 40.1, 200 mg,0.63 mmol, 1.0 equiv) was added pyridine (3 mL) and phosphorusoxychloride (438 μL, 4.7 mmol, 7.5 equiv) and the mixture was stirred atroom temperature for 45 hours. The solvents were removed in vacuo andthe residue was dissolved in DCM (5 mL) and washed with water (10 mL).The aqueous layer was extracted with DCM (5 mL) and the combinedorganics were washed with saturated sodium bicarbonate (2×10 mL), dried(Na₂SO₄), filtered and concentrated to obtain a mixture of the titlecompounds as a pale yellow oil (167 mg, 89%). m/z (ES+) 299 (M+H)⁺.

Compound 40.3. tert-Butyl 4-(4-cyanophenyl)azepane-1-carboxylate

To a 25 mL round bottom flask containing a mixture of tert-butyl4-(4-cyanophenyl)-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate andtert-butyl 5-(4-cyanophenyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate(compound 40.2, 167 mg, 0.56 mmol) was added 10% palladium on carbon (40mg) and ethyl acetate (6 mL). The system was purged with nitrogen thencharged with hydrogen and stirred at room temperature. After purging thesystem with nitrogen, the mixture was filtered through celite and thefiltrate was concentrated. The residue was purified by preparative TLCto obtain a colorless wax (77 mg, 45%). m/z (ES+) 245 (M minust-butyl+H)⁺.

Compound 40.4. 4-(Azepan-4-yl)benzonitrile

To a vial containing tert-butyl 4-(4-cyanophenyl)azepane-1-carboxylate(compound 40.3, 77 mg, 0.257 mmol, 1.0 equiv) was added DCM (500 μL) andtrifluoroacetic acid (198 μL, 2.57 mmol, 10 equiv) and the mixture wasstirred vented for 90 min. The mixture was diluted into ethyl acetate (5mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous wasadjusted to pH 10-11 and extracted with addition ethyl acetate until noproduct remained. The combined organics were dried (Na₂SO₄), filteredand concentrated to obtain the title compound as a yellow oil (51 mg,theoretical). m/z (ES+) 201 (M+H)⁺.

Compound 40.5. 4-(1-(3-Amino-4-methylbenzoyl)azepan-4-yl)benzonitrile

To a 4-mL vial was added 3-amino-4-methylbenzoic acid (27 mg, 0.18 mmol,1.0 equiv), 4-(azepan-4-yl)benzonitrile (compound 40.4, 40 mg, 0.2 mmol,1.1 equiv), hydroxybenzotriazole (39 mg of 20 wt % H2O, 0.23 mmol, 1.3equiv), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (44 mg, 0.23mmol, 1.3 equiv), DMF (1 mL) and N,N-diisopropylethylamine (93 μL, 0.54mmol, 3.0 equiv). The mixture was stirred at room temperature for 4hours then diluted into ethyl acetate (10 mL) and washed with brine (10mL). The aqueous was extracted with ethyl acetate (3 mL) and thecombined organics were washed with brine (10 mL), 1 M NaH₂PO₄ (5 mL) andbrine (10 mL). The organics were dried (Na₂SO₄), filtered andconcentrated to obtain the title compound as a brown solid (45 mg, 74%).m/z (ES+) 334 (M+H)⁺.

Compound 40.6.N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide

To a 4-mL vial containing4-(1-(3-amino-4-methylbenzoyl)azepan-4-yl)benzonitrile (compound 40.5,44 mg, 0.13 mmol, 1.0 equiv) was added dichloromethane (1 mL) andN,N-diisopropylethylamine (35 μL, 0.20 mmol, 1.5 equiv). A solution of6-fluoronicotinoyl chloride (22 mg, 0.14 mmol, 1.05 equiv) indichloromethane (1 mL) was added dropwise over about 2 minutes. Theresulting mixture was stirred at room temperature for 19 hours thendiluted with dichloromethane (5 mL) and washed with 1 M NaH₂PO₄ (3 mL),saturated sodium bicarbonate (3 mL) and brine (3 mL). The organics weredried (Na₂SO₄), filtered and concentrated to obtain the title compoundas a brown wax (64 mg, theoretical). m/z (ES+) 457 (M+H)⁺.

Compound 40.N-(5-(4-(4-Cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide

To a vial containingN-(5-(4-(4-cyanophenyl)azepane-1-carbonyl)-2-methylphenyl)-6-fluoronicotinamide(compound 40.6, 61 mg, 0.13 mmol) was added dimethylsulfoxide (1 mL) andisopropylamine (1 mL). The mixture was stirred at 35° C. for 2 hoursthen at room temperature for 16 hours followed by 35° C. for anadditional 4 hours. The excess isopropyl amine was removed in vacuo andthe remaining solution was purified by preparative HPLC to yield theproduct as an off white powder (TFA salt, 39 mg, 49%). m/z (ES+) 496(M+H)⁺.

Compound 41.1. 5-Nitro-2-(pyrrolidin-1-yl)pyridine

A mixture of 2-chloro-5-nitropyridine (1.58 g, 10.00 mmol, 1.00 equiv),pyrrolidine (710 mg, 10.00 mmol, 1.00 equiv) and potassium carbonate(2.76 g, 20.00 mmol, 2.00 equiv) in CH₃CN (20 mL) was stirred at 60° C.in an oil bath. After 2 h, the reaction mixture was allowed to reachambient temperature. The solids were filtered off and the filtrate wasconcentrated under reduced pressure. The residue was triturated with1×20 mL of petroleum ether to yield 1.8 g (93%) of the title compound asa yellow solid.

Compound 41.2. 6-(Pyrrolidin-1-yl)pyridin-3-amine

Around-bottom flask, containing a solution of5-nitro-2-(pyrrolidin-1-yl)pyridine (compound 40.1, 1.93 g, 10.00 mmol,1.00 equiv) in ethanol (30 mL) was purged with nitrogen. Palladium oncarbon (0.4 g, 10%, 60% water) was added. After further purging thesystem with nitrogen, the atmosphere was changed to hydrogen and theresulting mixture was stirred overnight at room temperature. Afterpurging the system with nitrogen, the solids were filtered off and thefiltrate was concentrated under reduced pressure and dried to yield 1.6g (98%) of the title compound as a brown solid.

Compound 41.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methyl-N-(6-(pyrrolidin-1-yl)pyridin-3-yl)benzamide

A mixture of compound 39.3 (528 mg, 1.52 mmol, 1.00 equiv) and HBTU (635mg, 2.28 mmol, 1.50 equiv) in DMF (30 mL) was stirred for 30 min at roomtemperature. To this was added 6-(pyrrolidin-1-yl)pyridin-3-amine(compound 41.2, 299 mg, 1.82 mmol, 1.20 equiv) and DIEA (50 mg). Theresulting mixture was stirred overnight at 60° C. in an oil bath. Aftercooling to room temperature, the reaction mixture was diluted with 50 mLof EtOAc and washed with 2×30 mL of NH₄Cl (aq., sat.) followed by 2×30mL of sodium bicarbonate (aq., sat.). The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-016(Waters)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, Water with 50 mmol NH₄HCO₃ and CH₃CN (10% CH₃CN up to 32%in 3 min, up to 51% in 20 min, up to 100% in 1 min, down to 10% in 1min); Detector, UV 220NMnm. The fractions containing pure compound werecombined and lyophilized to yield 50 mg (7%) of the title compound as asolid. m/z (ES+) 494 (M+H)⁺.

Compound 42.1. 5-Amino-2,4-dimethylbenzoic acid

A mixture of methyl 5-amino-2,4-dimethylbenzoate (1.2 g, 6.70 mmol, 1.00equiv) and sodium hydroxide (1.5 g, 37.50 mmol, 5.60 equiv) inmethanol/H₂O (20/20 mL) was stirred overnight at 50° C. After cooling toambient temperature, the organic phase was removed under reducedpressure. The pH of the remaining aqueous layer was adjusted to ˜4-5with hydrogen chloride (aq., 2 M). The resulting solids were collectedby filtration and dried to yield 1.0 g of a yellow solid.

Compound 42.2.4-(1-(5-Amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

A mixture of 5-amino-2,4-dimethylbenzoic acid (compound 42.1, 2.264 g,13.71 mmol, 1.00 equiv), HBTU (7.803 g, 20.59 mmol, 1.50 equiv),4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 2.8 g, 13.71mmol, 1.00 equiv), and DIEA (3.541 g, 27.45 mmol, 2.00 equiv) in DMF (50mL) was stiffed at room temperature. After 1 h, the mixture was dilutedwith 100 mL of EtOAc and washed with 1×100 mL of water followed by 1×100mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure to yield 3.51 g (73%) of thetitle compound as a white solid.

Compound 42.3.6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)nicotinamide

To a mixture of compound 42.2 (3.51 g, 9.99 mmol, 1.00 equiv) andtriethylamine (2.02 g, 19.96 mmol, 2.00 equiv) in DCM (50 mL) undernitrogen at 0° C. was added dropwise a solution of6-chloropyridine-3-carbonyl chloride (1.936 g, 11.00 mmol, 1.10 equiv)in DCM (50 mL). After stirring for 1 h at 0° C., the reaction mixturewas quenched by careful addition of 50 mL of water and extracted with2×50 mL of dichloromethane. The combined organic layers were washed with2×50 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to yield 4.41 g (90%) of the title compound as ayellow solid.

Compound 42.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicotinamide

A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv),propan-2-amine (472 mg, 7.99 mmol, 10.00 equiv), potassium carbonate(221 mg, 1.60 mmol, 2.01 equiv), KI (66.4 mg, 0.40 mmol, 0.50 equiv) inDMSO (10 mL) was heated at 100° C. in a sealed tube behind a blastshield. After 48, the mixture was allowed to reach ambient temperatureand was then diluted with 20 mL of EtOAc. The mixture was washed with1×20 mL of water followed by 1×20 mL of brine. The organic phase wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product (˜300 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH3CN (15.0%CH3CN up to 40.0% in 6 min, up to 100.0% in 2 min, down to 15.0% in 2min); Detector, uv 220&254 nm. The fractions containing pure compoundwere combined and lyophilized to yield 158 mg (39%) of the titlecompound as an off-white solid. m/z (ES+) 514 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD, ppm): δ 8.49 (s, 1H), 8.32 (d, J=9.9 Hz, 1H), 7.79 (d, J=8.1 Hz,2H), 7.67 (d, J=7.5 Hz, 2H), 7.40-7.22 (m, 2H), 7.07 (d, J=9.6 Hz, 1H),4.85 (m, 1H), 4.03 (m, 1H), 3.80-3.42 (m, 2H), 3.29 (m, 1H), 2.48-2.03(m, 9H), 1.95 (m, 1H), 1.39 (d, J=6.3 Hz, 6H).

Compound 43.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-morpholinonicotinamide

A mixture of compound 42.3 (392 mg, 0.80 mmol, 1.00 equiv), morpholine(348 mg, 3.99 mmol, 5.00 equiv), and potassium carbonate (221 mg, 1.60mmol, 2.01 equiv) in DMSO (10 mL) was stirred overnight at 100° C. in asealed tube behind a blast shield. After cooling to ambient temperature,the reaction mixture was diluted with 20 mL of EtOAc and was washed with1×20 mL of water followed by 1×20 mL of brine. The organic layer wasdried over anhydrous sodium sulfate and concentrated under reducedpressure. The crude product (300 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-002(Agilent)): Column,1#-PrepC-005(XBridge C18 19*150 186002979 170130047113 03), n; mobilephase, WATER WITH 0.05% TFA and CH₃CN (15.0% CH₃CN up to 50.0% in 10min, up to 100.0% in 1 min, hold 100.0% in 1 min, down to 15.0% in 2min); Detector, uv 220&254 nm. The fractions containing pure compoundwere combined and lyophilized to yield 106 mg (25%) of the titlecompound as a white solid. m/z (ES+) 542 (M+H)⁺.

Compound 44.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (219 mg, 50%). m/z (ES+) 544(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 8.56 (s with fine structure, 1H),8.41 (d with fine structure, J=9.9 Hz, 1H), 7.79 (br d, J=8.1 Hz, 2H),7.67 (br d, J=6.9 Hz, 2H), 7.44-7.19 (m, 3H), 4.88-4.73 (m, 1H), 3.94(t, J=5.0 Hz, 2H), 3.73 (t, J=5.0 Hz, 2H), 3.70-3.47 (m, 2H), 3.39 (s,3H), 3.36 (s, 3H), 3.36-3.21 (m, 1H), 2.46-2.22 (m, 6H), 2.22-1.85 (m,4H).

Compound 45.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(4-methylpiperazin-1-yl)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (180 mg, 44%). m/z (ES+) 555(M+H)⁺.

Compound 46.6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (180 mg, 44%). m/z (ES+) 512(M+H)⁺.

Compound 47.1.6-(1-(5-Amino-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)nicotinonitrile

The title compound was synthesized in a similar manner to that describedfor 42.2 and using compound 26.4 in place of compound 1.5 to yield abrown oil (280 mg, 89%).

Compound 47.2.6-Chloro-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 42.3 to yield a brown oil (350 mg, 91%).

Compound 47.6-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 43 to yield a white solid (187 mg, 54%). m/z (ES+) 527(M+H)⁺. ¹H NMR (300 MHz, DMSO-d₆): δ 9.88 (s, 1H), 9.06 (s, 1H), 8.59(d, J=1.8 Hz, 1H), 8.43 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 8.23 (d, J=9.3 Hz,1H), 7.81 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 7.17 (br s, 1H), 6.74 (d,J=9.0 Hz, 1H), 4.68-4.53 (m, 1H), 4.23 (t, J=7.7 Hz, 4H), 3.54-3.32 (m,2H), 3.22-3.05 (m, 1H), 2.59 (q, J=7.5 Hz, 2H), 2.50-2.38 (m, 2H),2.35-1.80 (m, 7H), 1.14 (t, 3H).

Compound 48.1. Methyl 2-ethyl-4-methylbenzoate

To a stirred mixture of ZnBr₂ (13 g, 57.72 mmol, 2.00 equiv) in THF (230mL) under nitrogen at 0° C. was added dropwise EtMgBr (19.5 mL, 3 M inTHF). After 30 minutes at 0° C., the temperature was lowered to −78° C.and Pd(dppf)Cl₂ (2 g, 2.73 mmol, 0.09 equiv) was added followed bydropwise addition of a solution of methyl 2-bromo-4-methylbenzoate (6.6g, 28.81 mmol, 1.00 equiv) in tetrahydrofuran (200 mL). The resultingmixture was allowed to slowly reach ambient temperature and stirredunder nitrogen overnight. The reaction mixture was quenched by thecareful addition of 20 mL NH₄Cl (aq., sat.) and extracted with 3×100 mLof ethyl acetate. The combined organic layers were washed with 1×200 mLof brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30) as eluent toyield 3.7 g (72%) of the title compound as a colorless oil.

Compound 48.2. 2-Ethyl-4-methylbenzoic acid

A mixture of compound 48.1, 3.7 g, 20.76 mmol, 1.00 equiv) and sodiumhydroxide (4 g, 100.01 mmol, 4.82 equiv) in methanol/H₂O (30/20 mL wasstirred overnight at 50° C. After cooling to ambient temperature, theorganic solvent was removed under reduced pressure. The pH of theresidual aqueous layer was adjusted to 3-4 with hydrogen chloride (aq.,1 M). The resulting precipitate was collected by filtration and dried toyield in 3.0 g (83%) of the title compound as a white solid.

Compound 48.3. 2-Ethyl-4-methyl-5-nitrobenzoic acid

To a stirred mixture of 2-ethyl-4-methylbenzoic acid (compound 48.2, 2g, 12.18 mmol, 1.00 equiv) in sulfuric acid (30 mL) at −10° C. was addeddropwise a solution of nitric acid (1.6 g, 16.50 mmol, 2.08 equiv) insulfuric acid (10 mL). After stirring for 30 min at −10° C., 200 mL ofH₂O/ice was carefully added and the resulting mixture was extracted with50 mL of ethyl acetate. The organic phase was washed with 2×50 mL ofbrine, dried over sodium sulfate, and concentrated under reducedpressure. The crude product was purified by re-crystallization fromethyl acetate/petroleum ether in the ratio 1:10 to yield 1.0 g (37%) of2-ethyl-4-methyl-5-nitrobenzoic acid as a light-yellow solid.

Compound 48.4. 5-Amino-2-ethyl-4-methylbenzoic acid

The title compound was synthesized from 48.3 (1 g, 4.78 mmol) using aprocedure similar to that described for the preparation of 1.9 to yieldthe title compound as a light pink solid (900 mg, 97%).

Compound 48.5.4-(1-(5-Amino-2-ethyl-4-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound 48.4, 100mg, 0.56 mmol, 1.00 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile(compound 11.2, 140 mg, 0.69 mmol, 1.23 equiv), HBTU (320 mg, 0.84 mmol,1.51 equiv), and DIEA (150 mg, 1.16 mmol, 2.08 equiv) in DMF (20 mL) wasstirred for 48 h at room temperature. Water (30 mL) was added and theresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were washed with 1×50 mL of brine, dried overNa₂SO₄, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with PE:EtOAc (1:1) toyield 130 mg (38%) of the title compound as a light yellow solid.

Compound 48.6.6-Chloro-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 42.3 and using compound 48.5 in place of compound 42.2 toyield a light yellow solid (200 mg, 87%).

Compound 48.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-6-(isopropylamino)nicotinamide

The title compound was synthesized in a similar manner to that describedfor compound 43 and using compound 48.6 in place of compound 42.3 toyield an off-white solid (32 mg, 30%). m/z (ES+) 528 (M+H)⁺.

Compound 49.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 500(M+H)⁺.

Compound 50.1. tert-Butyl5-cyano-5′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

To a stirred mixture of tert-butyl4-(5-cyanopyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (compound26.2, 500 mg, 1.65 mmol, 1.00 equiv) in pyridine (20 mL) was addeddropwise phosphoryl trichloride (2.5 g, 16.34 mmol, 9.90 equiv) at10-15° C. The resulting solution was stirred for 18 h at 15˜20° C. Thereaction was then carefully quenched by the addition of 20 mL of waterand extracted with 3×100 mL of ethyl acetate. The combined organicphases were washed with 2×50 mL of aqueous HCl (1 M) followed by 1×100mL of brine. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:100 to 1:7) as eluent to yield 0.3 g (64%) of the title compound as ayellow solid.

Compound 50.2. tert-butyl4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate.

Around-bottom flask, containing a solution of compound 50.1 (300 mg,1.05 mmol, 1.00 equiv) in ethyl acetate (20 mL), was purged withnitrogen gas. To the solution was then added palladium on carbon (40 mg,10%) and the flask was purged further with nitrogen gas. The atmospherewas then changed to hydrogen and the mixture was stirred for 16 h at15˜20° C. After purging the system with nitrogen, the solids wereremoved by filtration and the filtrate was concentrated under reducedpressure to yield 0.2 g (66%) of the title compound as a yellow oil.

Compound 50.3. 6-(Piperidin-4-yl)nicotinonitrile hydrochloride

Through a solution of tert-butyl4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate (compound 50.2, 200 mg,0.70 mmol, 1.00 equiv) in ethyl acetate (20 mL) was bubbled HCl gas. Theresulting mixture was stirred for 40 min at 5-10° C. The resultingprecipitate was collected by filtration and dried to yield 150 mg (97%)of the title compound as a white solid.

Compound 50.N-(5-(4-(5-Cyanopyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43 but using compound50.3 in place of compound 11.2. m/z (ES+) 483 (M+H)⁺.

Compound 51.1. tert-Butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

To a solution of 2,5-dibromopyridine (10 g, 42.55 mmol, 1.00 equiv) intetrahydrofuran (400 mL) under nitrogen at −78° C. was added dropwisen-BuLi (19 mL, 2.4 M in THF). After 1 h at −78° C., a solution oftert-butyl 4-oxopiperidine-1-carboxylate (9.5 g, 47.74 mmol, 1.12 equiv)in tetrahydrofuran (100 mL) was added dropwise. The resulting mixturewas stirred for an additional hour at −78° C. The reaction was thenwarmed to −30° C. and carefully quenched by the addition of 300 mL ofwater. The resulting mixture was extracted with 3×200 mL of ethylacetate and the combined organic layers were washed with 1×200 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:3) as eluent toyield 5 g (33%) of the title compound as a yellow solid.

Compound 51.2. tert-Butyl4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate

To a mixture of tert-butyl4-(6-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound51.1, 1 g, 2.81 mmol, 1.00 equiv) in DMF (50 mL) under nitrogen at 50°C. was added Zn(CN)₂ (400 mg, 3.42 mmol, 1.22 equiv) at 50° C. followedby Pd(PPh₃)₄ (200 mg, 0.17 mmol, 0.06 equiv) at 80° C. The resultingmixture was then stirred for 1 h at 120° C. After cooling to ambienttemperature, the reaction was quenched by the addition of 200 mL ofFeSO₄ (aq., sat.) and diluted with ethyl acetate. The resulting mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water, and ethyl acetate. The layers were separated and theaqueous phase was extracted with 2×100 mL of ethyl acetate. The combinedorganic layers were washed with 1×200 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:5-1:3) as eluent to yield 0.6 g (70%) of thetitle compound as a light yellow oil.

Compound 51.3. tert-Butyl6-cyano-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

To solution of tert-butyl4-(6-cyanopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate (compound51.2, 600 mg, 1.98 mmol, 1.00 equiv) in pyridine (15 mL) under nitrogenat 10-15° C. was carefully added POCl₃ (3 g, 19.74 mmol, 9.97 equiv).After stirring overnight under nitrogen in a water/ice bath, the mixturewas concentrated and the residue was dissolved in 50 mL of ethylacetate. The organic phase was washed with 1×50 mL of hydrogen chloride(aq. 1M) followed by 1×50 mL of sodium bicarbonate (aq.sat.). Theorganic layer was then dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:10) as the eluent to yield 0.26 g (46%) of the title compound as awhite solid.

Compound 51.4. tert-Butyl4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate.

A round-bottom flask, containing a solution of compound 51.3 (260 mg,0.91 mmol, 1.00 equiv) in ethyl acetate (40 mL) was purged with nitrogengas. To the solution was then added palladium on carbon (0.1 g, 10%, 60%water) and the flask was purged further with nitrogen gas. Theatmosphere was then changed to hydrogen and the mixture was stirred for16 h at 15˜20° C. After purging the system with nitrogen, the solidswere removed by filtration and the filtrate was concentrated underreduced pressure. The crude residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:5). This resultedin 0.18 g (69%) of the title compound as a colorless oil.

Compound 51.5. 5-(Piperidin-4-yl)picolinonitrile hydrochloride

Into a cooled (5-10° C.) solution of tert-butyl4-(6-cyanopyridin-3-yl)piperidine-1-carboxylate (51.4, 180 mg, 0.63mmol, 1.00 equiv) in ethyl acetate (30 mL) was bubbled hydrogen chloridegas. The mixture was stirred for 30 min at 5-10° C. and the resultingsolids were collected by filtration and dried to yield 0.11 g (78%) of5-(piperidin-4-yl)picolinonitrile hydrochloride as a white solid.

Compound 51.N-(5-(4-(6-Cyanopyridin-3-yl)piperidine-1-carbonyl)-2-methylphenyl)-6-(isopropylamino)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43 but using compound51.5 in place of compound 11.2. m/z (ES+) 483 (M+H)⁺.

Compound 52.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridazin-3-yl)-6-(isopropylamino)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 470(M+H)⁺.

Compound 53.2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 50. m/z (ES+) 482(M+H)⁺.

Compound 54.2-(Azetidin-1-yl)-N-(5-(4-(5-cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)pyrimidine-5-carboxamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 500(M+H)⁺.

Compound 55.6-(Azetidin-1-yl)-N-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethylphenyl)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 512(M+H)⁺.

Compound 56.6-(Azetidin-1-yl)-N-(5-(4-fluoro-4-(5-methoxypyridin-2-yl)piperidine-1-carbonyl)-2-methylphenyl)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 504(M+H)⁺.

Compound 57.6-(Azetidin-1-yl)-N-(2-chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)phenyl)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 518(M+H)⁺.

Compound 58.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinonicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 556(M+H)⁺.

Compound 60.N-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-((2-methoxyethyl)(methyl)amino)nicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 43. m/z (ES+) 558(M+H)⁺.

Compound 61.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-2-morpholinopyrimidine-5-carboxamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 544(M+H)⁺.

Compound 62.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-2-morpholinopyrimidine-5-carboxamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 558(M+H)⁺.

Compound 63.N-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-ethyl-4-methylphenyl)-6-morpholinonicotinamide

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 47. m/z (ES+) 557(M+H)⁺.

Compound 64.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea

A mixture of4-(1-(5-amino-2,4-dimethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 42.2, 150 mg, 0.43 mmol, 1.00 equiv), DIEA (560 mg, 4.33 mmol,10.15 equiv), and CO(OCC13)₂ (160 mg, 0.54 mmol, 1.26 equiv) in DCM (50mL) was stiffed under nitrogen at room temperature. After 0.5 h,(R)-(tetrahydrofuran-2-yl)methanamine (52 mg, 0.51 mmol, 1.20 equiv) wasadded. After stirring for 2 h at room temperature, the mixture waswashed with 2×50 mL of water and 1×50 mL of brine. The organic phase wasconcentrated under reduced pressure and the residue (˜200 mg) waspurified by prep-HPLC with the following conditions(1#-Pre-HPLC-006(Waters)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, WATER WITH 0.05% TFA and CH3CN (hold 5.0% CH3CN in 2 min,up to 35.0% in 1 min, up to 65.0% in 12 min, up to 100.0% in 1 min);Detector, UV 254/220 nm. The fractions containing pure compound werecombined and lyophilized to yield 110 mg (54%) of the title compound asa light yellow solid. m/z (ES+) 479 (M+H)⁺. ¹H NMR (300 MHz, DMSO, ppm):δ 7.91 (d, J=8.1 Hz, 2H), 7.77-7.69 (m, 4H), 7.04 (s, 1H), 6.68 (s, 1H),4.64 (m, 1H), 3.89-3.82 (m, 2H), 3.71 (m, 1H), 3.33-3.23 (m, 3H),3.11-3.09 (m, 2H), 2.18-2.03 (m, 8H), 1.97-1.84 (m, 4H), 1.57 (m, 1H).

Compound 65.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea

The title compound was synthesized in a similar manner to that describedfor compound 64 to yield a yellow solid (111 mg, 53%). m/z (ES+) 479(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.80 (d, J=8.1 Hz, 2H), 7.78-7.50 (m,3H), 7.13 (s, 1H), 4.88-4.72 (m, 1H), 3.94-8.82 (m, 1H), 3.82-3.68 (m,2H), 3.68-3.33 (m, 3H), 3.33-3.19 (m, 2H), 2.42-2.08 (m, 8H), 2.08-1.74(m, 4H), 1.74-1.54 (m, 2H).

Compound 66.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized in a similar manner to that describedfor compound 64 to yield a light yellow solid (105 mg, 53%). m/z (ES+)465 (M+H)⁺.

Compound 67.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea

The title compound was synthesized in a similar manner to that describedfor compound 64 but using compound 48.5 in place of compound 42.2. m/z(ES+) 493 (M+H)⁺.

Compound 68.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethyl-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea

The title compound was synthesized in a similar manner to that describedfor compound 64 but using compound 48.5 in place of compound 42.2. m/z(ES+) 493 (M+H)⁺.

Compound 69.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 70.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydro-2H-pyran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 71.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-cyclopentylurea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 449(M+H)⁺.

Compound 72.(R)-1-(5-(4-(5-Cyanopyridin-2-yl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 452(M+H)⁺.

Compound 73.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 451(M+H)⁺.

Compound 74.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methoxyphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 467(M+H)⁺.

Compound 75.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-fluorophenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 455(M+H)⁺.

Compound 76.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-ethylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 77.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-(trifluoromethyl)phenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 505(M+H)⁺.

Compound 78.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 465(M+H)⁺.

Compound 79.1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)-3-(2-methoxyethyl)urea

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 64. m/z (ES+) 439(M+H)⁺.

Compound 80.1. (R)-Tetrahydrofuran-3-yl 1H-imidazole-1-carboxylate

A solution of (R)-tetrahydrofuran-3-ol (500 mg, 5.68 mmol, 1.00 equiv)and CDI (2 g, 12.33 mmol, 2.17 equiv) in tetrahydrofuran (50 mL) wasstirred overnight under nitrogen at 60° C. After cooling to roomtemperature, the mixture was concentrated under reduced pressure. Theresidue was dissolved in 30 mL of DCM and washed with 1×50 mL of H₂O.The organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The crude residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:1) to yield 0.95 g(92%) of the title compound as a white solid.

Compound 80. (R)-Tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)carbamate

A mixture of compound 42.2 (200 mg, 0.57 mmol, 1.00 equiv),(R)-tetrahydrofuran-3-yl 1H-imidazole-1-carboxylate (80.1, 124 mg, 0.68mmol, 1.20 equiv), and DBU (2.6 mg, 0.02 mmol, 0.03 equiv) in DMF (50mL) was stirred for 16 h under nitrogen at 120° C. After cooling toambient temperature, the reaction was quenched by the addition of 200 mLof water. The resulting mixture was extracted with 3×100 mL of ethylacetate. The combined organic layers were washed with 1×100 mL of brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The residue (200 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, WATER WITH 0.05% TFA and CH₃CN (40.0%CH₃CN up to 45.0% in 8 min, hold 45.0% in 2 min, up to 100.0% in 1 min,down to 40.0% in 2 min); Detector, uv 220 254 nm 47.4 mg product wasobtained. The fractions containing pure compound were combined andlyophilized to yield 47.4 mg (18%) of the title compound as a whitesolid. m/z (ES+) 466 (M+H)⁺.

Compound 81. 1-Acetylpyrrolidin-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)carbamate

The title compound was synthesized in a similar manner to that describedfor compound 80 to yield a white solid (113 mg, 39%). m/z (ES+) 507(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.80 (d, J=8.1 Hz, 2H), 7.77-7.61 (m,2H), 7.52 & 7.33 (2 br singlets, amide rotamers, Ar—H, 1H), 7.17 (s,1H), 5.41-5.28 (m, 1H), 4.87-4.72 (m, 1H), 3.88-3.42 (m, 6H), 3.33-3.19(m, 1H), 2.42-1.82 (m, 15H).

Compound 82. (R)-Tetrahydrofuran-3-yl(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-methylphenyl)carbamate

The title compound was synthesized using readily available reagents andprocedures similar to those described for compound 80. m/z (ES+) 452(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 1 and2:

Cmpnd m/z # Compound Name Compound Structure (ES+) 83 2-(5-(4-(4-cyanophenyl)piperi- dine-1-carbonyl)-2,4- dimethylphenyl)-N,N-dimethyl-6,7- dihydro-3H- imidazo[4,5- c]pyridine-5(4H)- carboxamide

511 (M + H)⁺ 84 4-(1-(2,4-dimethyl- 5-(3,4,6,7- tetrahydropyrano(3,4-d]imidazol-2- yl)benzoyl)piperidin- 4-yl)-N,N- dimethylbenzamide

487 (M + H)⁺ 85 (2,4-dimethyl-5- (3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)phenyl)(4-(4- fluorophenyl)piper-idin-1-yl)methanone

434 (M + H)⁺ 86 (2,4-dimethyl-5- (3,4,6,7-tetrahydro-pyrano[3,4-d]imidazol- 2-yl)phenyl)(4-(4- (methylsulfonyl)phenyl)piperidin- 1-yl)methanone

494 (M + H)⁺ 87 (2,4-dimethyl-5- (3,4,6,7-tetrahydro-pyrano[3,4-d]imidazol- 2-yl)phenyl)(4-(4- methoxyphenyl) piperidin-1-yl)methanone

446 (M + H)⁺ 88 1-(2-(2,4-dimethyl- 5-(4-(4-(trifluoro-methyl)phenyl)piper- idine-l-carbonyl) phenyl)-6,7-dihydro-3H-imidazo[4,5- c]pyridin-5(4H)- yl)ethanone

525 (M + H)⁺ 89 4-(1-(5-(5- (cyclopropane- carbonyl)-4,5,6,7-tetrahydro-3H- imidazo[4,5- c]pyridin-2-yl)-2,4- dimethylbenzoyl)piperidin-4- yl)benzonitrile

508 (M + H)⁺ 90 1-(2-(5-(4-(4- fluorophenyl)piper- idine-1-carbonyl)-2,4-dimethylphenyl)- 6,7-dihydro-3H- imidazo[4,5- c]pyridin-5(4H)-yl)ethanone

475 (M + H)⁺ 91 4-(1-(4-methoxy-2- methyl-5-(3,4,6,7-tetrahydropyrano[3,4- d]imidazol-2- yl)benzoyl)piperidin-4-yl)benzonitrile

457 (M + H)⁺ 92 (4-(4- fluorophenyl)piper- idin-1-yl)(5-(5-(isopropylsulfonyl)- 4,5,6,7-tetrahydro- 3H-imidazo[4,5-c]pyridin-2-yl)-2,4- dimethylphenyl) methanone

539 (M + H)⁺ 93 1-(2-(5-(4-(4- fluorophenyl)piper- idine-1-carbonyl)-2,4-dimethylphenyl)- 6,7-dihydro-3H- imidazo[4,5-c]pyridin-5(4H)-yl)-2-methyl- propan-1-one

503 (M + H)⁺ 94 (2,4-dimethyl-5- (3,4,6,7-tetrahydro-pyrano[3,4-d]imidazol- 2-yl)phenyl)(4- phenylpiperidin-1- yl)methanone

416 (M + H)⁺ 95 methyl 2-(5-(4-(4- cyanophenyl)piper-idine-1-carbonyl)-2,4- dimethylphenyl)-6,7- dihydro-3H-imidazo[4,5-c]pyridine- 5(4H)-carboxylate

498 (M + H)⁺ 96 4-(1-(2,4-dimethyl- 5-(5-propionyl-4,5,6,7-tetrahydro-3H- imidazo[4,5-c]pyridin- 2-yl)benzoyl)piperidin-4-yl)benzonitrile

496 (M + H)⁺ 97 4-(1-(5-(5- isobutyryl-4,5,6,7- tetrahydro-3H-imidazo[4,5-c] pyridin-2-yl)-2,4- dimethylbenzoyl) piperidin-4-yl)benzonitrile

510 (M + H)⁺ 98 (2,4-dimethyl-5- (3,4,6,7-tetrahydro-pyrano[3,4-d]imidazol- 2-yl)phenyl)(4-(p- tolyl)piperidin-1-yl)methanone

430 (M + H)⁺ 99 4-(1-(2,4-dimethyl- 5-(4,5,6,7- tetrahydro-1H-benzo[d]imidazol-2- yl)benzoyl)piperidin- 4-yl)benzonitrile

439 (M + H)⁺ 100 4-(1-(2,3-dimethyl- 5-(3,4,6,7- tetrahydropyrano[3,4-d]imidazol-2- yl)benzoyl)piperi- din-4-yl)benzonitrile

441 (M + H)⁺ 101 4-(1-(2-chloro- 3-(3,4,6,7-tetra- hydropyrano[3,4-d]imidazol-2-yl) benzoyl)piperidin- 4-yl)benzonitrile

447 (M + H)⁺ 102 4-(1-(3-(5-isopropyl- 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin- 2-yl)-4-methyl- benzoyl)piperidin-4-yl)benzonitrile

468 (M + H)⁺ 103 methyl 2-(5-(4-(4- cyanophenyl)piper-idine-1-carbonyl)- 2-methylphenyl)- 6,7-dihydro-3H-imidazo[4,5-c]pyridine- 5(4H)-carboxylate

484 (M + H)⁺ 104 (2,4-dimethyl-5-(5- methyl-4,5,6,7- tetrahydro-3H-imidazo[4,5-c]pyridin- 2-yl)phenyl)(4-(4- (trifluoromethyl)phenyl)piperidin-1- yl)methanone

497 (M + H)⁺

Compound 105.4-(1-(2,4-Dimethyl-5-(6-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 20,except compound 11.2HCl salt was used in place of compound 1.5. m/z(ES+) 523 (M+H)⁺.

Compound 106.4-(1-(5-(6-(Azetidin-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 20,except 4-fluoro-2-methylbenzoic acid and azetidine were used in place of2,4-dimethylbenzoic acid and pyrrolidine respectively. m/z (ES+) 495(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compound 20:

Cmpnd m/z # Compound Name Compound Structure (ES+) 107 2-(5-(4-(4-cyanophenyl)piper- idine-1-carbonyl)- 2,4-dimethyl- phenyl)-1H-benzo[d]imidazole- 5-carboxylic acid

479 (M + H)⁺ 108 4-(1-(5-(3H- imidazo[4,5-c]pyridin- 2-yl)-2,4-dimethyl-benzoyl)piperidin-4- yl)benzonitrile

436 (M + H)⁺ 109 2-(5-(4-(4- cyanophenyl)piper- idine-1-carbonyl)-2,4-dimethylphenyl)- N,N-dimethyl-1H- benzo[d]imidazole- 5-carboxamide

506 (M + H)⁺ 110 2-(5-(4-(4- cyanophenyl)piper- idine-1-carbonyl)-2,4-dimethylphenyl)- 1H-benzo[d]imidazole- 5-carboxamide

478 (M + H)⁺ 111 2-(5-(4-(4- cyanophenyl)piper- idine-1-carbonyl)-2,4-dimethylphenyl)- 1H-benzo[d]imidazole- 5-carbonitrile

460 (M + H)⁺ 112 4-(1-(2,4-dimethyl- 5-(4-(oxetan-3-yl)-3H-imidazo[4,5-c]pyridin- 2-yl)benzoyl)piper- idin-4-yl)benzonitrile

492 (M + H)⁺ 113 4-(1-(5-(4- methoxy-3H- imidazo[4,5-c]pyridin-2-yl)-2,4-dimethyl- benzoyl)piperidin- 4-yl)benzonitrile

466 (M + H)⁺ 114 4-(1-(2,4-dimethyl-5- (4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin- 2-yl)benzoyl)piperidin- 4-yl)benzonitrile

452 (M + H)⁺ 115 4-(1-(5-(4- (azetidin-1-yl)-3H- imidazo[4,5-c]pyridin-2-yl)-2,4-dimethyl- benzoyl)piperidin-4- yl)benzonitrile

491 (M + H)⁺ 116 4-(1-(2,4-dimethyl- 5-(6-(oxetan-3-yloxy)-3H-imidazo[4,5-c]pyridin- 2-yl)benzoyl)piperidin- 4-yl)benzonitrile

508 (M + H)⁺ 117 4-(1-(2,4-dimethyl- 5-(4-(pyrrolidin-1-yl)-3H-imidazo[4,5-c]pyridin- 2-yl)benzoyl)piperidin- 4-yl)benzonitrile

505 (M + H)⁺

Compound 118.1. Tetramethyl2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate

A mixture of (E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide(2.89 g, 10 mmol), dimethyl malonate (3.43 mL, 30 mmol), t-BuOK (2.24 g,20 mmol) in anhydrous t-BuOH (20 mL) was heated at 50° C. for 4 h. Aftercooling to room temperature, the reaction mixture was poured intosaturated aqueous NH₄Cl and extracted with CH₂Cl₂ (3×). The combinedorganic layer was dried over MgSO₄, filtered, and then concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(10%, 20%, 30%, then 40%) to give the title compound as a clear oil(3.255 g, 85% yield).

Compound 118.2. 3-(4-Methoxyphenyl)pentanedioic acid and3-(4-hydroxyphenyl)pentanedioic acid

A mixture of tetramethyl2-(4-methoxyphenyl)propane-1,1,3,3-tetracarboxylate (compound 118.1, 6.0g, 15.7 mmol) in concentrated HCl (37%, 80 mL) was heated under refluxovernight. After cooling to room temperature, the suspension wasfiltered. The filtrate was washed with water and dried under vacuum togive 2.66 g product as a mixture of 3-(4-methoxyphenyl)pentanedioic acid(major, LCMS observed [M−H]⁻ 237) and 3-(4-hydroxyphenyl)pentanedioicacid (minor, LCMS observed [M−H]⁻ 223).

Compound 118.3. Dimethyl 3-(4-methoxyphenyl)pentanedioate

A mixture of the product (compound 118.2) obtained from the previousstep (2.66 g), K₂CO₃ (6.56 g, 47.5 mmol) and CH₃I (3 mL, 47.5 mmol) inDMF (10 mL) was heated at 50° C. in a pressure tube overnight. Aftercooling to room temperature, the reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc (3×). The combinedorganic extract was dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(20%, 30%, 40%, then 50%) to give the title compound as a clear oil (2.0g, 48% yield over two steps).

Compound 118.4. Dimethyl3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate

To a solution of LDA (18.8 mmol) in THF (60 mL) at −78° C. was added asolution of dimethyl 3-(4-methoxyphenyl)pentanedioate (2.0 g, 7.52 mmol)in THF (10 mL) dropwise. After stirring at −78° C. for 1 h, the dryice-acetone bath was removed. The reaction mixture was stirred for 30min before being cooled to −78° C. Solid AgCl (2.2 g, 15.4 mmol) wasadded all at once. The reaction mixture was stirred at −78° C. for 1 hand then room temperature overnight. Saturated aqueous NH₄Cl was added.The mixture was vigorously stirred for 10 min. The suspension wasfiltered through celite. The filtrate was extracted with EtOAc (3×). Thecombined organic extract was dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatographywith EtOAc in hexane (10%, 15%, 20%, then 30%) to give the titlecompound as a pale yellow solid (0.87 g, 44% yield). ¹HNMR (CDCl₃, 400Hz) δ 7.09 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.82 (s, 3H), 3.77(s, 6H), 3.17 (t, J=7.6 Hz, 1H), 2.36 (d, J=7.6 Hz, 2H).

Compound 118.5. 3-(4-Methoxyphenyl)cyclopropane-1,2-dicarboxylic acid

A mixture of dimethyl 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylate(0.88 g, 3.33 mmol) and LiOH (2M in H₂O, 10 mL) in THF (30 mL) wasstirred at 55° C. overnight. After cooling to room temperature, thereaction mixture was poured into 1N HCl and extracted with EtOAc (3×).The combined organic extract was dried over MgSO₄, filtered, andconcentrated to give the title compound as a light yellow solid.

Compound 118.6. 6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione.

A mixture of 3-(4-methoxyphenyl)cyclopropane-1,2-dicarboxylic acid(crude product from the previous step) in Ac₂O (20 mL) was heated underreflux for 1 h. Excess Ac₂O was removed under reduced pressure. Thecrude product was used in the next step without further purification.

Compound 118.7.3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione

A mixture of 6-(4-Methoxyphenyl)-3-oxabicyclo[3.1.0]hexane-2,4-dione(crude product from the previous step) and (4-methoxyphenyl)methanaminewas heated at 180° C. for 1.5 h. After cooling to room temperature, thereaction mixture was dissolved in CH₂Cl₂ and purified by flash columnchromatography with EtOAc in hexane (20%, 30%, then 40%) to give thetitle compound as a yellow solid (0.71 g, 63% yield over three steps).MS [M+H]⁺: 338.

Compound 118.8.3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane

A mixture of3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione(0.86 g, 2.6 mmol), NaBH₄ (0.296 g, 7.8 mmol) and BF₃ etherate (1.0 mL,7.8 mmol) in THF was heated under reflux overnight. After cooling to 0°C., a solution of piperazine (2 g) in H₂O (20 mL) was added. The mixturewas stirred at room temperature for 2 h, poured into H₂O and extractedwith EtOAc (3×). The combined organic extract was dried over MgSO₄,filtered and then concentrated. The residue was purified by flash columnchromatography with EtOAc in hexane (10%, 20%, then 30%) to give a whitesolid. To a suspension of the solid in THF (20 mL) and H₂O (10 mL) wasadded piperazine (3 g). After heating the mixture under refluxovernight, it was poured into brine and extracted with EtOAc (3×). Thecombined organic extract was dried over MgSO₄, filtered and concentratedto give the title compound as white solid (0.51 g, 65% yield). MS[M+H]⁺: 310.

Compound 118.9. 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane

To a solution of(1R,5S,6S)-3-(4-Methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane(0.5 g, 1.6 mmol) in DCE (30 mL) at 0° C. was added 1-chloroethylchloroformate (0.21 mL, 1.9 mmol, 1.2 equiv). The reaction mixture wasstirred at 0° C. for 30 min, heated under reflux for 1 h and thenconcentrated under reduced pressure. MeOH (20 mL) was added. Theresulting mixture was heated under reflux for 40 min and thenconcentrated. The residue was purified by preparative TLC to give thetitle compound as a white crystalline solid (155 mg, 51% yield). MS[M+H]⁺: 190.

Compound 118.10.(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone

A mixture of 6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane (0.124 g,0.82 mmol), 3-amino-4-methylbenzoic acid (0.155 g, 0.82 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.172g, 0.90 mmol), 1-hydroxybenzotriazole (˜20% H₂O, 0.122 g, 0.90 mmol) anddiisopropylethylamine (0.71 mL, 4.1 mmol) in DMF (3 mL) was stirred atroom temperature overnight. The reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc (3×). The combinedorganic extract was dried over MgSO₄, filtered and concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(60%, then 100%) to give the title compound as a white foam (0.15 g, 57%yield).

Compound 118.11.6-Chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide

To a solution of(3-Amino-4-methylphenyl)(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexan-3-yl)methanone(150 mg, 0.47 mmol) and Et₃N (0.25 mL, 1.8 mmol) in CH₂Cl₂ (4 mL) at 0°C. was added 6-chloronicotinoyl chloride (106 mg, 0.6 mmol). The icebath was removed after the addition. The reaction mixture was stirred atroom temperature for 1.5 h and then purified by flash columnchromatography with EtOAc in hexane (60%, then 100%) to give the titlecompound as a white foam (0.172 g, 80% yield). MS [M+H]⁺: 462, 464.

Compound 118.6-(Isopropylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide

A mixture of6-chloro-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide(compound 118.11, 0.107 g, 0.23 mmol) and isopropylamine (1.5 mL) inDMSO (1.5 mL) was heated at 120° C. in a sealed pressure tube overnight.After cooling to room temperature, the reaction mixture was poured intosaturated aqueous NaHCO₃ and extracted with EtOAc (3×). The combinedorganic extract was dried over MgSO₄, filtered and concentrated. Theresidue was triturated with hexane to give the title compound as a whitepowder (40 mg, 36% yield). MS [M+H]⁺: 485. ¹H-NMR (DMSO-d6, 400 Hz) δ9.63 (s, 1H), 8.69 (d, J=3 Hz, 1H), 7.95-7.90 (m, 1H), 7.55-7.51 (m,1H), 7.39-7.30 (m, 2H), 7.10-7.03 (m, 3H), 6.84 (d, J=9.2 Hz, 2H), 6.52(d, J=9.2 Hz, 1H), 4.17-4.07 (m, 2H), 3.85-3.77 (m, 1H), 3.74 (s, 3H),3.65-3.51 (m, 2H), 2.30 (s, 3H), 1.87 (s, 2H), 1.69 (t, J=3.7 Hz, 1H),1.20 (d, J=7.2 Hz, 6H).

Compound 119.6-(Ethylamino)-N-(5-(6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)nicotinamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound118. MS [M+H]⁺: 471. ¹HNMR (DMSO-d6, 400 Hz) δ 9.62 (s, 1H), 8.66 (d,J=2.4 Hz, 1H), 7.91 (dd, J=2.4, 9.0 Hz, 1H), 7.50 (s, 1H), 7.34-7.24 (m,2H), 7.18 (t, J=6.0 Hz, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.81 (d, J=8.8 Hz,2H), 6.50 (d, J=9.2 Hz, 1H), 4.08 (d, J=12.4 Hz, 1H), 3.81-3.75 (m, 1H),3.70 (s, 3H), 3.59 (d, J=11.2 Hz, 1H), 3.52 (d, J=13.2 Hz, 1H),3.37-3.30 (m, 2H), 2.26 (s, 3H), 1.84 (s, 2H), 1.66 (t, J=3.2 Hz, 1H),1.16 (t, J=8.4 Hz, 3H).

Compound 120.1-(5-(6-(4-Methoxyphenyl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compounds 64 and118. m/z (ES+) 436 (M+H)⁺.

Compound 121.1.4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile

A solution of 3-amino-4-methylbenzoic acid (1.36 g, 9.0 mmol),(4-(piperidin-4-yl)benzonitrile HCl salt (compound 1.5, 2.0 g, 9.0mmol), EDCI (1.89 g, 9.9 mmol), HOBT (1.66 g, 9.9 mmol, with 20% H₂O)and DIEA (3.13 ml, 18.0 mmol) in DMF (50 ml) was stirred at roomtemperature overnight. The reaction mixture was poured into cold water(300 ml) and off white solids precipitated. The precipitate wasfiltered, washed with water and dried under reduced pressure in an ovento yield 2.88 g (100%) of the title compound. m/z (ES+) 320 (M+H)⁺.

Compound 121.6-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)amino)-N-isopropylnicotinamide

A mixture of 6-chloro-N-isopropylnicotinamide (0.055 g, 0.26 mmol),4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1, 0.1 g,0.31 mmol), K₂CO₃ (0.171 g, 1.24 mmol), Pd(OAc)₂ (6.7 mg, 0.03 mmol) andthe ligand (10.2 mg, 0.03 mmol) in toluene (5 mL) was heated at 90° C.under argon for 3 h. After cooling to room temperature, the reactionmixture was diluted with H₂O and extracted with EtOAc. The combinedorganic extract was dried over MgSO₄, filtered, and concentrated. Theresidue was purified by flash column chromatography with EtOAc in hexane(60%, 80%, then 100%) to give the title compound as an off-white powderafter lyophilization from CH₃CN/H₂O (11.2 mg, 9% yield). m/z (ES+) 482(M+H)⁺.

Compound 122.4-(1-(4-Methyl-3-β5-(4-methylpiperazine-1-carbonyl)pyridin-2-yl)amino)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 121replacing K₂CO₃ with t-BuONa. m/z (ES+) 524 (M+H)⁺.

Compound 123.N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-6-(pyrrolidin-1-yl)nicotinamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 43and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. m/z (ES+) 481 (M+H)⁺.

Compound 124.1-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)-3-isobutylurea

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. m/z (ES+) 406 (M+H)⁺.

Compound 125.N-(4-(4-(4-Cyanophenyl)piperidine-1-carbonyl)pyridin-2-yl)pyrrolidine-1-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64and using 2-aminoisonicotinic acid in place of 3-amino-4-methylbenzoicacid. m/z (ES+) 404 (M+H)⁺.

Compound 126.N-(3-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2,4-dimethylphenyl)-6-(isopropylamino)nicotinamide

The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 43 andusing 3-amino-2,6-dimethylbenzoic acid in place of3-amino-4-methylbenzoic acid. m/z (ES+) 514 (M+H)⁺.

Compound 127.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2-ethyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 39.m/z (ES+) 445 (M+H)⁺.

Compound 128.4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-methyl-3-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 38). m/z (ES+) 416 (M+H)⁺.

Compound 129.4-(1-(3-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 38.m/z (ES+) 402 (M+H)⁺.

Compound 130.1. Methyl 5-carbamothioyl-2,4-dimethylbenzoate

To a round-bottom flask was added a solution of methyl5-cyano-2,4-dimethylbenzoate (compound 2.3, 1.78 g, 9.41 mmol, 1.00equiv) in tetrahydrofuran/H₂O (30/3 mL). O,O′-diethyl dithiophosphate(3.30 g, 17.7 mmol, 2.00 equiv) was added and the resulting mixture wasstirred for 2 days at 85° C. (CAUTION: significant gas evolutionoccurs—this and all other reactions described herein should be carriedout in well ventilated fume hoods). After cooling to ambienttemperature, the mixture was extracted with 2×50 mL of ethyl acetate.The combined organic layers were dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:10) aseluent to furnish 1.20 g (57%) of the title compound as a yellow solid.

Compound 130.2. Methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate.

To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound130.1, 3.10 g, 12.5 mmol, 1.00 equiv, 90%) in tetrahydrofuran (30 mL)was added CH₃I (3.95 g, 27.8 mmol, 2.00 equiv) and the resulting mixturewas stirred overnight at 25° C. The organic layer was washed with 2×30mL of Na₂S₂O₄ (aq.) and 1×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 2.10 g (64%) ofmethyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate as a yellow oil.

Compound 130.3. Methyl 2-(tetrahydrofuran-3-yl)acetate

A mixture of 2-(tetrahydrofuran-3-yl)acetic acid (2.00 g, 15.4 mmol,1.00 equiv) and sulfuric acid (2 mL) in methanol (20 mL) was stiffed for3 h at 80° C. in an oil bath. After cooling to ambient temperature, themixture was diluted with 50 mL of ether and washed with 2×20 mL ofwater, 2×20 mL of sodium bicarbonate (aq., sat. Note: gas evolution),and 2×20 mL of brine. The organic phase was then dried over anhydroussodium sulfate and concentrated in vacuo to yield 1.50 g (68%) of thetitle compound as a yellow oil.

Compound 130.4. 2-(Tetrahydrofuran-3-yl)acetohydrazide

To a round-bottom flask was added a solution of methyl2-(tetrahydrofuran-3-yl)acetate (compound 130.3, 1.50 g, 10.4 mmol, 1.00equiv) and NH₂NH₂. H₂O (1.04 g, 20.8 mmol, 2.00 equiv) in methanol (15mL). The resulting mixture was stiffed overnight at 80° C. in an oilbath. After cooling to ambient temperature, the mixture was concentratedin vacuo to yield 1.20 g (80%) of the title compound as a yellow oil.

Compound 130.5. Methyl2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate

To a round-bottom flask was added a solution of2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4, 1.20 g, 8.32mmol, 1.50 equiv) in acetic acid (4 mL). Methyl2,4-dimethyl-5-(methylsulfanyl)carboximidoylbenzoate (compound 130.2,1.30 g, 5.48 mmol, 1.00 equiv) was added and the resulting mixture wasstirred overnight at 100° C. in an oil bath. After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue wasdiluted with 50 mL of ethyl acetate, then washed with 2×20 mL of waterand 2×20 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether(0:1-1:10-1:1) as eluent to furnish 0.600 g (35%) of the title compoundas a yellow solid.

Compound 130.6.2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoicacid

To a round-bottom flask was added a solution of methyl2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoate(compound 130.5, 600 mg, 1.90 mmol, 1.00 equiv) in methanol (10 mL). Asolution of sodium hydroxide (381 mg, 9.53 mmol, 5.00 equiv) in water (5mL) was added and the resulting mixture was stirred for 3 h at 70° C. inan oil bath. After cooling to room temperature, the organic solvent wasthen removed under reduced pressure and the pH of the remaining aqueousphase was adjusted to 3-4 with hydrogen chloride (aq., 1 M). Theresulting solids were collected via filtration and dried in an ovenunder reduced pressure to yield 0.500 g (87%) of the title compound as ayellow solid.

Compound 130.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

A mixture of compound 130.6 (200 mg, 0.660 mmol, 1.00 equiv), EDCI (253mg, 1.32 mmol, 2.00 equiv), DMAP (243 mg, 1.99 mmol, 3.00 equiv), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 148 mg,0.660 mmol, 1.00 equiv) in DMF (5 mL) was stirred for 3 h at 25° C.,then diluted with 50 mL of ethyl acetate. The organic layer was washedwith 2×10 mL of water, 2×10 mL of brine, dried over anhydrous sodiumsulfate and concentrated in vacuo. The crude product (˜300 mg) waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (28% CH₃CN up to 52% in 8min, up to 100% in 1 min, down to 28% in 1 min); Detector, Waters 2489254&220 nm. The fractions containing pure compound were combined andlyophilized to yield 168 mg (52%) of the title compound as a whitesolid. m/z (ES+) 470 (M+H)⁺. ¹H-NMR (400 Hz, CD₃OD): δ 7.68 (d, J=8.0Hz, 2H), 7.61 (s, 1H), 7.50-7.49 (m, 2H), 7.33-7.31 (m, 1H), 4.90-4.88(m, 1H), 3.95-3.92 (m, 2H), 3.90-3.81 (m, 1H), 3.79-3.77 (m, 1H),3.69-3.55 (m, 1H), 3.28-3.25 (m, 1H), 3.03-2.94 (m, 4H), 2.81-2.73 (m,1H), 2.53 (s, 3H), 2.43 and 2.33 (2s, amide rotamers, ArCH₃, 3H),2.19-2.15 (m, 1H), 2.13-2.05 (m, 1H), 1.94-1.68 (m, 4H).

Compound 131.4-(1-(5-(5-(2-Methoxyethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 3-methoxypropanehydrazide (compound 143.1) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)444 (M+H)⁺.

Compound 132.4-(1-(5-(5-(Methoxymethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-methoxyacetohydrazide (compound 190.6) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)430 (M+H)⁺.

Compound 133.1. (R)-Tetrahydrofuran-2-carbohydrazide

A mixture of (R)-tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol,1.00 equiv), EDCI (12.4 g, 64.6 mmol, 1.50 equiv) and HOBt (8.70 g, 64.4mmol, 1.50 equiv) in dichloromethane (100 mL) was stirred for 30 min at25° C. To the mixture was then added hydrazine (2.00 g, 62.4 mmol, 1.50equiv) dropwise. The resulting mixture was stirred overnight at 25° C.The solids were removed by filtration, and the filtrate was concentratedin vacuo to furnish 25.0 g (crude) of(R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.

Compound 133.(R)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using (R)-tetrahydrofuran-2-carbohydrazide (compound133.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 446 (M+H)⁺.

Compound 134.1. Ethyl 2-hydrazinyl-2-oxoacetate

To a round-bottom flask was added a solution of diethyl oxalate (10.0 g,68.4 mmol, 1.00 equiv) in ethanol (100 mL). Hydrazine hydrate (2.75 g,85.8 mmol, 1.00 equiv) was added and the resulting mixture was stirredfor 3 h at 80° C. After cooling to ambient temperature, the solids wereremoved via filtration and the filtrate was concentrated in vacuo toyield 8.00 g (80%) of the title compound as a colorless oil.

Compound 134.2. 2-Hydrazinyl-N-methyl-2-oxoacetamide

To a round-bottom flask was added a solution of ethyl2-hydrazinyl-2-oxoacetate (compound 134.1, 300 mg, 2.04 mmol, 1.00equiv, 90%) in methanol (10 mL). Methyl amine (10 mL, 40% in water) wasadded and the resulting mixture was stirred overnight at 70° C. Aftercooling to ambient temperature, the solids were collected by filtrationand dried to yield 250 mg (94%) of the title compound as a white solid.

Compound 134.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N-methyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound130, using compound 134.2 instead of compound 130.4. m/z (ES+) 443(M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.62-7.43 (m,3H), 7.32 (s, 1H), ˜4.9 (1H partially obscured by water peak), 3.73-3.58(m, 1H), 3.32-3.18 (m, 1H partially obscured by methanol solvent peak),3.07-1.91 (m, 5H), 2.58 (s, 3H), 2.43 & 2.33 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.93 (m, 1H), 1.93-1.52 (m, 3H).

Compound 135.1. 2-Hydrazinyl-N,N-dimethyl-2-oxoacetamide

To a round-bottom flask was added ethyl 2-hydrazinyl-2-oxoacetate(compound 134.1, 2.00 g, 13.6 mmol, 1.00 equiv, 90%). Dimethylamine (10mL) was added to the reaction, and then the reaction was stirredovernight at 70° C. in an oil bath. The mixture was cooled to roomtemperature and concentrated in vacuo to yield 1.50 g (76%) of the titlecompound as a colorless oil.

Compound 135.5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-4H-1,2,4-triazole-3-carboxamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-hydrazinyl-N,N-dimethyl-2-oxoacetamide (compound135.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 457 (M+H)⁺.

Compound 136.1. (S)-Tetrahydrofuran-2-carbohydrazide

To a round-bottom flask was added a solution of(S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 23.3 mmol, 1.00 equiv,90%) in dichloromethane (40 mL). NH₂NH₂ (2 mL, 2.00 equiv), HOBt (5.20g, 38.5 mmol, 1.50 equiv), and EDCI (7.50 g, 39.1 mmol, 1.50 equiv) wereadded and the resulting mixture was stirred overnight at 25° C. Thesolids were removed by filtration, and the filtrate was concentrated invacuo to furnish 2.50 g (74%) of (S)-tetrahydrofuran-2-carbohydrazide asa yellow oil.

Compound 136.(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using (S)-tetrahydrofuran-2-carbohydrazide (compound136.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 456 (M+H)⁺.

Compound 137.1. Methyl tetrahydro-2H-pyran-4-carboxylate

To a solution of tetrahydro-2H-pyran-4-carboxylic acid (520 mg, 4.00mmol, 1.00 equiv) in methanol (50 mL) was added PTSA (35.0 mg, 0.200mmol). The resulting mixture was stirred overnight at 80° C. in an oilbath, then cooled to ambient temperature and concentrated in vacuo. Theresidue was diluted with 30 mL of water and extracted with 3×30 mL ofDCM. The combined organic layers were dried over anhydrous magnesiumsulfate and concentrated in vacuo. This resulted in 500 mg (87%) ofmethyl tetrahydro-2H-pyran-4-carboxylate as a colorless oil.

Compound 137.2. Tetrahydro-2H-pyran-4-carbohydrazide

To a round-bottom flask was added a solution of methyltetrahydro-2H-pyran-4-carboxylate (compound 137.1, 5.00 g, 31.2 mmol,1.00 equiv, 90%) in methanol (50 mL). Hydrazine hydrate (5.20 g, 83.2mmol, 3.00 equiv) was added and the resulting mixture was stiffedovernight at 40° C. in an oil bath. After cooling to ambienttemperature, the mixture was concentrated in vacuo to yield 4.00 g (80%)of tetrahydro-2H-pyran-4-carbohydrazide as a white solid.

Compound 137.4-(1-(2,4-Dimethyl-5-(5-(tetrahydro-2H-pyran-4-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using tetrahydro-2H-pyran-4-carbohydrazide (compound137.2) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound130.4). m/z (ES+) 470 (M+H)⁺.

Compound 138.1. 2-(Tetrahydrofuran-2-yl)acetohydrazide

To a round-bottom flask was added a solution of ethyl2-(tetrahydrofuran-2-yl)acetate (2.00 g, 12.6 mmol, 1.00 equiv) inethanol (20 mL). NH₂NH₂.H₂O (1.27 g, 25.4 mmol, 2.00 equiv) was added tothe reaction. The resulting solution was stirred overnight at 80° C. inan oil bath, then cooled to room temperature and concentrated in vacuo.This resulted in 2.10 g (92%) of 2-(tetrahydrofuran-2-yl)acetohydrazideas a yellow oil.

Compound 138.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-2-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-(tetrahydrofuran-2-yl)acetohydrazide (compound138.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide(compound130.4). m/z (ES+) 470 (M+H)⁺.

Compound 139.1. 2-Cyanoacetohydrazide

To a solution of NH₂NH₂.H₂O (3.50 g, 70.0 mmol, 1.00 equiv) in a solventmixture of ethanol and Et₂O (35/35 mL) at 0° C. was added dropwise asolution of methyl 2-cyanoacetate (7.00 g, 70.6 mmol, 1.00 equiv) inethanol (5 mL). The resulting mixture was stirred for 3 h at roomtemperature, then washed with 2×30 mL of ether. The solids werecollected by filtration to yield 5.00 g (68%) of 2-cyanoacetohydrazideas a white solid.

Compound 139.4-(1-(5-(5-(cyanomethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 2-cyanoacetohydrazide (compound 139.1) instead of2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 425(M+H)⁺. ¹H-NMR (300 Hz, CD₃OD): δ 7.70 (d, J=8.4 Hz, 2H), 7.54-7.42 (m,3H), 7.35 (s, 1H), 4.87-4.80 (m, 1H), 4.12 (s, 2H), 3.77-3.65 (m, 1H),3.27-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.55 (s, 3H), 2.43 and 2.33 (2singlets, amide rotamers, ArCH₃, 3H), 2.05-2.00 (m, 1H), 1.83-1.76 (m,3H).

Compound 140.1. 3-cyanopropanehydrazide

To a round-bottom flask was added a solution of NH₂NH₂.H₂O (1.25 g, 25.1mmol, 1.00 equiv) in ether/EtOH (8/8 mL). To this was added methyl3-cyanopropanoate (2.84 g, 25.1 mmol, 1.00 equiv) dropwise. Theresulting solution was stirred for 2 h at room temperature, thenconcentrated in vacuo. This resulted in 1.40 g (49%) of3-cyanopropanehydrazide as a colorless oil.

Compound 140.4-(1-(5-(5-(2-cyanoethyl)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130), using 3-cyanopropanehydrazide (compound 140.1) insteadof 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+)439 (M+H)⁺. ¹H-NMR (300 Hz, CD₃OD): δ 7.68 (d, 2H), 7.58-4.47 (m, 3H),7.30 (s, 1H), 4.89-4.80 (m, 1H), 3.65-3.62 (m, 1H), 3.32-3.30 (m, 1H),3.15 (t, 2H), 3.03-2.95 (m, 4H), 2.50 (s, 3H), 2.42 and 2.32 (2singlets, amide rotamers, ArCH₃, 3H), 2.03-2.00 (m, 1H), 1.83-1.78 (m,3H).

Compound 141.4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-ylmethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 130). m/z (ES+) 456 (M+H)⁺.

Compound 142.1. Methyl 4-cyclopropyl-2-methylbenzoate

To a solution of methyl 4-bromo-2-methylbenzoate (5.00 g, 20.7 mmol,1.00 equiv, 95%) in a mixture of toluene and H₂O (20 mL/1 mL) were addedpotassium carbonate (6.10 g, 44.1 mmol, 2.00 equiv), cyclopropylboronicacid (2.30 g, 26.8 mmol, 1.20 equiv), Pd(dppf)Cl₂ (900 mg, 1.23 mmol,0.05 equiv), and Pd(OAc)₂ (250 mg, 1.12 mmol, 0.05 equiv). The reactionmixture was purged with nitrogen and stirred at 80° C. overnight. Aftercooling to room temperature, the mixture was then concentrated in vacuo.The resulting residue was purified via silica gel column chromatographywith ethyl acetate/petroleum ether (1:50) as eluent to yield 2.68 g(61%) of methyl 4-cyclopropyl-2-methylbenzoate as a colorless oil.

Compound 142.2. Methyl 4-cyclopropyl-5-iodo-2-methylbenzoate

To a solution of methyl 4-cyclopropyl-2-methylbenzoate (compound 142.1,2.68 g, 13.4 mmol, 1.00 equiv, 95%) in AcOH (50 mL) were added NaIO₄(1.51 g, 7.08 mmol, 0.50 equiv), I₂ (3.58 g, 14.1 mmol, 1.00 equiv), andsulfuric acid (201 mg, 2.01 mmol, 0.15 equiv, 98%). The reaction mixturewas stirred at 110° C. overnight. After cooling to ambient temperature,100 mL of water was added. The resulting mixture was diluted with 100 mLof ethyl acetate, then washed with 3×30 mL of Na₂S₂O₃ (aq., sat.) and1×30 mL of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified via silicagel column chromatography with ethyl acetate/petroleum ether (1/50) aseluent to yield 2.00 g (45%) of methyl4-cyclopropyl-5-iodo-2-methylbenzoate as a colorless oil.

Compound 142.3. Methyl 5-cyano-4-cyclopropyl-2-methylbenzoate

To a solution of methyl 4-cyclopropyl-5-iodo-2-methylbenzoate (compound142.2, 2.00 g, 6.01 mmol, 1.00 equiv, 95%) in DMF (16 mL) was addedZn(CN)₂ (890 mg, 7.58 mmol, 1.27 equiv) and Pd(PPh₃)₄ (731 mg, 0.630mmol, 0.11 equiv). The resulting solution was stirred at 100° C. undernitrogen overnight. After cooling to ambient temperature, the reactionwas then quenched by the addition of 100 mL of FeSO₄ (aq., sat.) anddiluted with ethyl acetate. The resulting mixture was stirred vigorouslythen filtered through celite and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×100 mL of ethyl acetate. The combined organic phases were driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified via silica gel column chromatography with ethylacetate/petroleum ether (1/50) as eluent to yield 1.10 g (81%) of methyl5-cyano-4-cyclopropyl-2-methylbenzoate as a light yellow oil.

Compound 142.4. Methyl 5-carbamothioyl-4-cyclopropyl-2-methylbenzoate.

To a solution of methyl 5-cyano-4-cyclopropyl-2-methylbenzoate (compound142.3, 1.65 g, 7.28 mmol, 1.00 equiv, 95%) in a mixture oftetrahydrofuran and H₂O (20 mL/5 mL) was addedO,O′-diethylphosphorodithioate (3.79 g, 22.3 mmol, 2.00 equiv). Theresulting mixture was stirred at 80° C. overnight (CAUTION: significantgas evolution occurs—this and all other reactions described hereinshould be carried out in well ventilated fume hoods). After cooling toambient temperature, the reaction was quenched with 100 mL of water. Theresulting solution was extracted with 100 mL of ethyl acetate. Thecombined organic layers were washed with 3×30 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. The residue waspurified via silica gel column chromatography with ethylacetate/petroleum ether (1/5) as eluent to furnish 0.880 g (46%) ofmethyl 5-carbamothioyl-4-cyclopropyl-2-methylbenzoate as a white solid.

Compound 142.5. Methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate

To a round-bottom flask was added a solution of methyl5-carbamothioyl-4-cyclopropyl-2-methylbenzoate (compound 142.4, 880 mg,3.35 mmol, 1.00 equiv, 95%) in tetrahydrofuran (10 mL). Iodomethane(1.00 g, 7.05 mmol, 2.00 equiv) was added and the resulting mixture andstirred at room temperature overnight. The mixture was then concentratedin vacuo to yield 0.800 g (86%) of methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate as acolorless liquid.

Compound 142.6. Methyl 3-(dimethylamino)propanoate hydrochloride

To a round-bottom flask was added a solution of3-(dimethylamino)propanoic acid (2.00 g, 17.1 mmol, 1.00 equiv) inmethanol (60 mL). Hydrogen chloride (g) was bubbled into the reactionmixture and the resulting solution was stirred for 4 h at 25° C.Concentration of the reaction mixture in vacuo afforded 2.00 g of titlecompound as a colorless oil.

Compound 142.7. 3-(Dimethylamino)propanehydrazide

To a solution of methyl 3-(dimethylamino)propanoate hydrochloride(compound 142.6, 2.00 g, 15.3 mmol, 1.00 equiv) in methanol (40 mL) wasadded hydrazine hydrate (6 mL, 6.00 equiv). The reaction mixture wasstirred at 70° C. for 3 h. The mixture was concentrated in vacuo andthen dissolved in 50 mL of H₂O and washed with 2×10 mL of ethyl acetate.The aqueous layers were combined and concentrated in vacuo to afford1.30 g (65%) of 3-(dimethylamino)propanehydrazide as a colorless oil.

Compound 142.8. Methyl4-cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate

A solution of 3-(dimethylamino)propanehydrazide (compound 142.7, 1.20 g,9.15 mmol, 5.00 equiv) and methyl4-cyclopropyl-2-methyl-5-(methylsulfanyl) carboximidoylbenzoate(compound 142.5, 600 mg, 2.28 mmol, 1.00 equiv) in AcOH (30 mL) wasstirred at 80° C. overnight. After cooling to ambient temperature, thepH was adjusted to 8-9 with sodium hydroxide (aq., 1 M). The resultingmixture was extracted with 2×100 mL of ethyl acetate and the combinedorganic layers were concentrated in vacuo. The residue was purified viasilica column chromatography with dichloromethane/methanol (10/1) aseluent to give 504 mg (67%) of the title compound as a white solid.

Compound 142.9.4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

To a solution of compound 142.8 (200 mg, 0.610 mmol, 1.00 equiv) in amixture of methanol and H₂O (6 mL/3 mL) was added sodium hydroxide (97.6mg, 2.44 mmol, 4.00 equiv) in water (1 mL). After stirring at 60° C.overnight, the organic solvent was removed under reduced pressure. Theresidual aqueous layer was washed with 20 mL of ethyl acetate. The pHwas then adjusted to 4-5 with HCl (aq., 3 M), and the resulting mixturewas extracted with ethyl acetate (3×20 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated in vacuo to afford 280 mg (73%) ofthe title compound as a brown solid.

Compound 142.4-(1-(4-Cyclopropyl-5-(5-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of compound 2661.9 (250 mg, 0.800 mmol, 1.00 equiv) inN,N-dimethylformamide (3 mL) were added 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 175 mg, 0.790 mmol, 1.00 equiv), EDCI (302mg, 1.58 mmol, 2.00 equiv), and DMAP (194 mg, 1.59 mmol, 2.00 equiv).The resulting mixture was stirred at 25° C. overnight and then dilutedwith water. The mixture was extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were washed with 2×20 mL of NH₄Cl(aq) and 2×20mL of brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified via silica gel column chromatographywith dichloromethane/methanol (10/1) as eluent. The product (˜150 mg)was further purified by Prep-HPLC with the following conditions[(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm;mobile phase, water with 0.03% NH₃H₂O and CH₃CN (32.0% CH₃CN up to 47.0%in 7 min, up to 100.0% in 1 min, down to 32.0% in 1 min); Detector,Waters 2489 254&220 nm]. The fractions containing pure compound werecombined and lyophilized to yield 70.3 mg (18%) of the title compound asa white solid. m/z (ES+) 483 (M+H)⁺.

Compound 143.1. 3-Methoxypropanehydrazide

A mixture of methyl 3-methoxypropanoate (5.0 g, 42.33 mmol) andhydrazine (1.36 g, 42.33 mmol) was heated at 50° C. for two hours. Themixture was concentrated and dried under reduced pressure to give theproduct as a clear oil. Yield: 5.0 g, 100%. m/z (ES+) 119 (M+H)⁺. ¹H NMR(400 MHz, Chloroform-d) δ 7.86 (br, 1H), 4.05-3.71 (m, 2H), 3.63 (t,2H), 3.34 (s, 3H), 2.42 (t, 2H).

Compound 143.4-(1-(4-Cyclopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 142and using compound 143.1 in place of 142.7. m/z (ES+) 471 (M+H)⁺.

Compound 144.4-(1-(4-Cyclopropyl-5-(5-((dimethylamino)methyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142. m/z (ES+) 469 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=6.3 Hz,2H), 7.49 (d, J=6.0 Hz, 2H), 7.47 & 7.39 (2 singlets, amide rotamers,Ar—H, 1H), 7.03 (s, 1H), ˜4.9 (1H partially obscured by water peak),3.74 (s, 2H), 3.72-3.57 (m, 1H), 3.32-3.22 (m, 1H partially obscured bymethanol solvent peak), 3.00 (t with fine structure, J=8.9 Hz, 2H),2.49-2.27 (m, 2H), 2.10-1.98 (m, 2H), 1.93-1.51 (m, 3H), 1.05-0.90 (m,2H), 0.79-0.64 (m, 2H).

Compound 145.4-(1-(5-(5-(Azetidin-1-ylmethyl)-4H-1,2,4-triazol-3-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142. m/z (ES+) 481 (M+H)⁺.

Compound 146.2-(5-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-N,N-dimethylacetamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142. m/z (ES+) 497 (M+H)⁺.

Compound 147.1. Methyl 4-ethyl-2-methylbenzoate

To a stirred mixture of ZnBr₂ (4.50 g, 20.0 mmol, 2.00 equiv) intetrahydrofuran (50 mL) under nitrogen at 0° C. was added EtMgBr (6.6mL, 2.00 equiv, 3M in THF) dropwise. After stiffing for 30 min at 0° C.,the temperature was lowered to −78° C. and Pd(dppf)Cl₂ (1.08 g, 1.48mmol, 0.30 equiv) was added followed by a solution of methyl4-bromo-2-methylbenzoate (compound 152.1, 2.30 g, 10.0 mmol, 1.00 equiv)in tetrahydrofuran (20 mL). The resulting mixture was stirred for 30 minat −78° C., warmed to room temperature, and stirred overnight. Thereaction mixture was carefully quenched with 60 mL of NH₄Cl (aq.) andextracted with 3×50 mL of ethyl acetate. The combined organic phaseswere dried (Na₂SO₄) and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (1:100-1:5) as eluent to furnish 1.50 g (84%) of methyl4-ethyl-2-methylbenzoate as a brown oil.

Compound 147.2.4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound142.9 and using compounds 147.1 and 143.1 instead of compounds 142.1.and 142.7.

Compound 147.4-(1-(4-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of compound (147.2, 100 mg, 0.350 mmol, 1.00 equiv) in DMF(10 mL) under nitrogen were added EDCI (132 mg, 0.690 mmol, 2.00 equiv)and DMAP (85.0 mg, 0.700 mmol, 2.00 equiv). The resulting mixture wasstirred 30 min at 25° C. followed by the addition of4-(piperidin-4-yl)benzonitrile (compound 1.5, 129 mg, 2.77 mmol, 2.00equiv). The reaction mixture was stirred for 25 h at 25° C., thenquenched with 40 mL of ice water, and extracted with 3×50 mL of ethylacetate. The combined organic layers were washed with 1×50 mL of brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:1) as eluent. The crude product (50 mg)was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm;mobile phase, water with 0.03% NH₃H₂O and CH₃CN (33% CH₃CN up to 52% in10 min, up to 100% in 1 min, down to 33% in 1 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 20.2 mg (12%) of the title compound as a whitesolid. m/z (ES+) 458 (M+H)⁺.

Compound 148.4-(1-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation compound 147and using compound 11.2HCl salt instead compound 1.5. m/z (ES+) 476(M+H)⁺.

Compound 149.4-(1-(5-(5-(Ethoxymethyl)-4H-1,2,4-triazol-3-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds147 and 148. m/z (ES+) 476 (M+H)⁺.

Compound 150.4-(1-(4-Ethyl-2-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(I-(4-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 147). m/z (ES+) 470 (M+H)⁺.

Compound 151.4-(1-(4-Ethyl-5-(5-(isopropoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds147 and 148. m/z (ES+) 490 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.78 (d,2H), 7.69-7.34 (m, 4H), 4.82-4.78 (m, 1H), 4.72 (s, 2H), 3.80 (quintet,1H), 3.57-3.55 (m, 2H), 3.30-3.25 (m, 1H), 2.94 (q, 2H), 2.46 and 2.35(2 singlets, amide rotamers, ArCH₃, 3H), 2.35-2.1 (m, 3H), 2.0-1.95 (m,1H), 1.30 (d, 6H), 1.14 (t, 3H).

Compound 152.1. Methyl 4-bromo-2-methylbenzoate

To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) overabout 3 minutes (mildly exothermic). The resulting mixture was refluxedfor 4 hours. After cooling to room temperature, the reaction mixture wascarefully quenched into saturated aqueous NaHCO₃ (100 mL)(note—significant gas evolution) and extracted with dichloromethane (200mL×1 then 50 mL×1). The combined organic phases were washed with amixture of brine/saturated NaHCO₃ (9:1)(50 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to obtain the title compound as acolorless oil (5.28 g, 97%). ¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.0Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H),2.58 (s, 3H).

Compound 152.2. Methyl 4-cyclobutyl-2-methylbenzoate

Cyclobutylzinc(II) bromide (50 ml, 0.5 M in THF, 25.0 mmol) was added toa mixture of methyl 4-bromo-2-methylbenzoate (compound 152.1, 5.2 g,22.7 mmol) and PdCl₂(dppf)CH₂Cl₂ (1.85 g, 2.27 mmol). The mixture wasdegassed and the flask was filled with argon through a balloon. Themixture was heated at 65° C. under argon for 24 hours. The mixture wascooled to 0° C. and quenched with water (10 ml). The mixture was dilutedwith EtOAc (200 ml), washed with water then with brine. The EtOAc layerwas dried (Na₂SO₄), concentrated under reduced pressure, and purifiedusing column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1).Yield: 4.1 g, clear oil, 89.1%. ¹H NMR (400 MHz, Chloroform-d) δ 7.86(d, 1H), 7.12-7.02 (m, 2H), 3.88 (s, 3H), 3.59-3.48 (m, 1H), 2.59 (s,3H), 2.35 (m, 2H), 2.22-1.96 (m, 3H), 1.86-1.84 (m, 1H).

Compound 152.3. Methyl 4-cyclobutyl-5-iodo-2-methylbenzoate

N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portionwise to asolution of methyl 4-cyclobutyl-2-methylbenzoate (compound 152.2, 3.2 g,15.6 mmol) in concentrated sulfuric acid (25 ml) at 0° C. The mixturewas stiffed at 0° C. for 30 min and at RT for 2 hours. The mixtureturned very thick. The mixture was cooled to 0° C. again and MeOH (30ml) was added. The mixture was heated at 60° C. for 2 hours. Themethanol was removed under reduced pressure and the residue was pouredinto ice water (100 ml). The mixture was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, then aq. 1N NaHCO₃(note-significant gas evolution), dried (Na₂SO₄) and concentrated. Theresidue was purified using column (silica gel) chromatography(hexanes:EtOAc 30:1 to 20:1). Yield: 4.17 g, light yellow oil, 81%. ¹HNMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H),3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H),1.82-1.79 (m, 1H).

Compound 152.4. Methyl 5-cyano-4-cyclobutyl-2-methylbenzoate

A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound152.3, 4.17 g, 12.64 mmol), Zn(CN)₂ (2.96 g, 25.21 mmol) and Pd(PPh₃)₄(0.73 g, 0.63 mmol) in DMF (30 ml) was degassed and the flask was filledwith argon through a balloon. The mixture was heated at 100° C. underargon overnight. After cooling to ambient temperature, the mixture wasquenched with saturated aq. FeSO₄ (20 ml) and diluted with EtOAc (200ml). The greenish solid was removed by filtration through celite. Thefiltrate was partitioned between water and EtOAc. The EtOAc layer waswashed with brine, dried (Na₂SO₄), and concentrated. The residue waspurified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to20:1). Yield: 2.55 g, white solid, 88%. ¹H NMR (400 MHz, Chloroform-d) δ8.16 (s, 1H), 7.28 (s, 1H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 2.68 (s,3H), 2.55-2.45 (m, 2H), 2.27-2.04 (m, 3H), 1.89-1.87 (m, 1H).

Compound 152.5. Methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate.

To a round-bottom flask were added methyl5-cyano-4-cyclobutyl-2-methylbenzoate

(compound 152.4, 3.63 g, 0.015 mol), O,O′-diethyl dithiophosphate (10mL) and water (1 mL). The reaction mixture was heated to 80° C. for 3hours (CAUTION: significant gas evolution occurs—this and all otherreactions described herein should be carried out in well ventilated fumehoods). After cooling to room temperature, the reaction mixture waspartitioned between ethyl acetate (50 mL) and water (50 mL). Thecombined organic layers were washed successively with saturated aqueousNaHCO₃ (50 mL) and brine (50 mL), dried over Na₂SO₄, and concentrated invacuo. Purification by SiO₂ flash chromatography (hexanes/ethylacetate=80/20 to 50/50) afforded methyl5-carbamothioyl-4-cyclobutyl-2-methylbenzoate as a yellow solid (3.06 g,78% yield). m/z (ES+) 264 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 7.93 (s,1H), 7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s,3H), 2.64 (s, 3H), 2.40 (m, 2H), 2.29-2.15 (m, 2H), 2.12-2.00 (m, 1H),1.95-1.84 (m, 1H).

Compound 152.6. Methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate

To a round-bottom flask was added methyl5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 152.5, 861 mg,3.27 mmol) in THF (10 mL). Iodomethane (912 mg, 6.42 mmol) was addeddropwise and the reaction mixture was stiffed at room temperature for 7hours. The reaction mixture was concentrated in vacuo and purified bySiO₂ flash chromatography (ethyl acetate to ethyl acetate/methanol=95/5)to afford methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate as a yellowishoil (807 mg, 89% yield). m/z (ES+) 278 (M+H)⁺. ¹H NMR (400 MHz,DMSO-d₆): δ 7.67 (s, 1H), 7.40 (s, 1H), 3.88-3.71 (m, 4H), 2.57 (s, 3H),2.44 (s, 3H), 2.22-2.19 (m, 2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H),1.82-1.70 (m, 1H).

Compound 152.7. Methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate

To a round-bottom flask were added methyl4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate (compound152.6, 556 mg, 0.002 mol) and acetohydrazide (223 mg, 0.003 mol) in 6 mLacetic acid. The reaction mixture was heated to 90° C. for 3 hours.After cooling to room temperature, the reaction mixture was partitionedbetween water (50 mL) and ethyl acetate (50 mL). The organic layer waswashed with brine (2×50 mL), dried over Na₂SO₄, and concentrated invacuo. Purification via SiO₂ flash chromatography (hexanes/ethylacetate=50/50 to 30/70) afforded the title compound as a white solid(243 mg, 43% yield). m/z (ES+) 286 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ8.23 (s, 1H), 7.32 (s, 1H), 4.24-4.05 (m, 1H), 3.89 (s, 3H), 2.69 (s,3H), 2.54 (s, 3H), 2.23-2.20 (m, 2H), 2.16-2.05 (m, 2H), 2.05-1.88 (m,1H), 1.88-1.71 (m, 1H).

Compound 152.8.4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid

To a solution of methyl4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoate(compound 152.7, 240 mg, 0.842 mmol) in methanol (5 mL) was addedaqueous NaOH (6 mL, 1M). The resulting mixture was heated to 50° C. for6 hours. After cooling to ambient temperature, the reaction mixture wasacidified with 1N HCl to pH 2 and extracted with ethyl acetate (3×50mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, and concentrated in vacuo to afford4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid(260 mg, quantitative) as a white solid. m/z (ES+) 272 (M+H)⁺.

Compound 152.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution of4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid(compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL) were added4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 232 mg,1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285 mmol), andDIEA (367.7 mg, 2.85 mmol). The resulting mixture was stirred at roomtemperature for 16 hours. The mixture was quenched with saturatedaqueous NaHCO₃ (20 mL) and extracted with ethyl acetate (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered, and concentrated in vacuo. Purification via SiO₂column chromatography (dichloromethane/methanol=95/5) afforded4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrileas a white solid (193 mg, 44% yield). m/z (ES+) 440 (M+H)⁺. ¹H NMR (300MHz, CD₃OD): δ 7.69 (d, J=5.4 Hz. 2H), 7.56-7.30 (m, 4H), 1 protonobscured by methanol solvent peak, 4.10-3.98 (m, 1H), 3.64 (t, J=10.7Hz, 1H), 3.33-3.21 (m, 1H), 3.00 (t, J=8.9 Hz, 2H), 2.58 (s, 3H), 2.48and 2.38 (2 singlets, amide rotamers, ArCH₃, 3H), 2.28-1.92 (m, 6H),1.92-1.55 (m, 4H). ¹H NMR (400 MHz, DMSO-d₆): δ 13.66 (s, 1H), 7.77 (d,J=8.0 Hz, 2H), 7.62-7.34 (m, 4H), 4.78-4.63 (m, 1H), 4.31 (br s, 1H),3.45 (br s, 1H), 3.15 (app t, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H),2.44-1.80 (m, 12H), 1.80-1.37 (m, 4H).

Compound 153.4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), but using 3-methoxypropanehydrazide (compound 143.1) inplace of acetohydrazide. m/z (ES+) 484 (M+H)⁺, 967 (2M+H)⁺. ¹H NMR (400MHz, Chloroform-d) δ 11.50-11.33 (br s, 1H), 7.66-7.44 (m, 3H),7.33-7.27 (m, 3H), 4.98 (d, 1H), 4.24-4.12 (m, 1H), 3.78 (t, 2H), 3.70(d, 1H), 3.44 (s, 3H), 3.14-3.03 (m, 3H), 2.90-2.75 (m, 2H), 2.42 and2.34 (2 singlets, amide rotamers, ArCH₃, 3H), 2.17 (d, 2H), 2.08-1.88(m, 3H), 1.84-1.51 (m, 5H).

Compound 154.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152) but using 2-methoxyacetohydrazide (compound 190.6) inplace of acetohydrazide. m/z (ES+) 470 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃):δ 12.15 (br s, 1H), 7.64-7.57 (m, 2H), 7.43 & 7.33 (2 singlets, amiderotamers, Ar—H, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (s, 1H), 5.04-4.92 (m,1H), 4.65 (s, 2H), 4.18-4.03 (m, 1H), 3.63 (br d, J=13.2 Hz, 1H), 3.51(s, 3H), 3.08 (t with fine structure, J=12.8 Hz, 1H), 2.93-2.77 (m, 2H),2.38 & 2.30 (2 singlets, amide rotamers, ArCH₃, 3H), 2.25-1.84 (m, 6H),1.84-1.43 (m, 4H).

Compound 155.4-(1-(4-Cyclobutyl-5-(5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152but using 2-hydroxyacetohydrazide in place of acetohydrazide. m/z (ES+)456 (M+H)⁺.

Compound 156.4-(1-(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 153), using 4-(4-fluoropiperidin-4-yl)benzonitrilehydrochloride salt (compound 11.2HCl salt) instead of4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5). m/z(ES+) 501.8 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.46 (br s, 1H),7.75-7.45 (m, 3H), 7.49 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 4.89 (br d,J=13.2 Hz, 1H), 4.28-4.15 (m, 1H), 3.79 (t, J=6.0 Hz, 2H), 3.70-3.45 (m,2H), 3.46 (s, 3H), 3.31-3.17 (m, 1H), 3.13 (t, J=6.0 Hz, 2H), 2.45 &2.38 (2 br singlets, amide rotamers, Ar—CH₃, 3H), 2.30-1.68 (m, 10H).

Compound 157.(4-Cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 153), using 4-(4-(trifluoromethyl)phenyl)piperidinehydrochloride salt instead of 4-(piperidin-4-yl)benzonitrilehydrochloride salt (compound 1.5). m/z (ES+) 527 (M+H)⁺. ¹H NMR (400MHz, Chloroform-d) δ 11.30-11.10 (br, 1H), 7.60-7.47 (m, 3H), 7.35-7.28(m, 3H), 5.10-4.93 (m, 1H), 4.24-4.13 (m, 1H), 3.78 (t, 2H), 3.70 (d,1H), 3.45 (s, 3H), 3.12 t, 2H), 3.15-3.05 (m, 1H), 2.90-2.75 (m, 2H),2.44 and 2.35 (2 singlets, amide rotamers, ArCH₃, 3H), 2.25-2.13 (m,2H), 2.13-1.85 (m, 4H), 1.87-1.66 (m, 4H).

Compound 158.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using compound 11.2HCl salt instead of compound 1.5. m/z(ES+) 458 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.66 (s, 1H), 7.66 (d,2H), 7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46 (brs, 1H), 3.16 (dd, 1H), 3.04-2.78 (m, 2H), 2.38 and 2.36 (2 singlets,amide rotamers, ArCH₃, 3H), 2.35-2.27 (m, 3H), 2.22-1.82 (m, 6H),1.81-1.56 (m, 3H).

Compound 159.(4-Cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 483 (M+H)⁺.

Compound 160.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152and using propionohydrazide instead of acetohydrazide. m/z (ES+) 454(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.75-7.43 (m, 3H), 7.40-7.17(m, 3H), 5.18-4.81 (m, 1H), 4.30-3.91 (m, 1H), 3.84-3.55 (m, 1H),3.21-2.99 (m, 1H), 2.92-2.69 (m, 4H), 2.40 and 2.32 (2 singlets, amiderotamers, ArCH₃, 3H), 2.25-1.84 (m, 7H), 1.83-1.42 (m, 3H), 1.32 (t,3H).

Compound 161.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 472 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ7.79-7.57 (m, 2H), 7.57-7.18 (m, 4H), 4.86 (dd, 1H), 4.14 (s, 1H),3.62-3.40 (m, 4H), 3.22 (t, 1H), 2.77 (q, 2H), 2.31 & 2.41 (2 singlets,amide rotamers, 3H), 2.29-1.47 (m, 8H), 1.30 (t, 3H).

Compound 162.4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 468 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d⁶) δ 13.67(s, 1H), 7.77 (d, 2H), 7.49-7.47 (m, 3H), 7.36 (s, 1H), 4.72 (d, 1H),4.29 (s, 1H), 3.46 (d, 1H), 3.12 (m, 2H), 2.98-2.75 (m, 2H), 2.31 (d,3H), 2.23-1.81 (m, 6H), 1.83-1.36 (m, 4H), 1.31 (d, 6H).

Compound 163.4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 486 (M+H)⁺.

Compound 164.1.4-(1-(4-Cyclobutyl-5-(5-isopropyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.7 and using propionohydrazide instead of acetohydrazide.

Compound 164.2. Methyl4-cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate

Methyl 4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate(compound 164.1, 87 mg, 0.29 mmol) was dissolved in methanol anddichloromethane (1:1 v/v) (6 ml). ((Trimethylsilyl)methyl)diazomethane(2.0 M in ether) (220 ul, 0.44 mmol) was added. The mixture was stiffedfor 16 hours and quenched with HOAc (300 ul). The volatiles were removedin vacuo to afford an oil (85 mg). The residue was carried as crude ontothe next step without further purification. m/z (ES+) 314 (M+H)⁺.

Compound 164.4-(1-(4-Cyclobutyl-5-(5-ethyl-N-methyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound (mixture of N-methyl isomers) was prepared usingstandard chemical manipulations and procedures similar to those used forpreparation of compound 152 and using compound 164.2 instead of compound152.7. m/z (ES+) 468 (M+H)⁺.

Compound 165.4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 494.0 (M+H)⁺.

Compound 166.4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of441-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152). m/z (ES+) 476 (M+H)⁺.

Compound 167.4-(1-(4-Cyclobutyl-5-(5-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-[1-[4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl]-4-piperidyl]benzonitrile(compound 152). m/z (ES+) 494 (M+H)⁺.

Compound 168.1. Methyl 4-cyclobutylbenzoate

To a stirred mixture of ZnBr₂ (83.0 g, 368.53 mmol, 4.00 equiv) in THF(500 mL) under nitrogen at 0° C. was added a solution ofbromo(cyclobutyl)magnesium (242 mL, 364 mmol, 1.5 M in THF) dropwiseduring 20 min. To the resulting mixture were added Pd(dppf)Cl₂ (2.00 g,0.10 equiv) and methyl 4-bromobenzoate (20 g, 93.00 mmol, 1.00 equiv) at−40° C. The resulting mixture was stirred at −40° C. for 1 h undernitrogen, and then carefully quenched with 500 mL of NH₄Cl(aq., sat.).The mixture was extracted with 3×500 mL of ethyl acetate. The combinedorganic layers were washed with 3×500 mL of brine, then dried overanhydrous sodium sulfate, and concentrated under reduced pressure toyield 18.0 g (crude) of the title compound as a light yellow oil.

Compound 168.2. Methyl 4-cyclobutyl-3-iodobenzoate

To a solution of methyl 4-cyclobutylbenzoate (168.1, 2.00 g, 10.5 mmol,1.00 equiv) in acetic acid (30 mL) were carefully added sodium periodate(1.00 g, 4.68 mmol, 0.50 equiv), iodine (3.00 g, 11.8 mmol, 1.10 equiv)and sulfuric acid (0.15 g, 0.15 equiv). The resulting mixture wasstirred overnight at 100° C. After cooling to room temperature, thereaction was then quenched by carefully adding 30 mL of Na₂S₂O₃ (aq.,sat.) and the resulting mixture was extracted with 3×20 mL of ethylacetate. The combined organic layers were washed with 3×20 mL of brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to yield 1.50 g (45%) of the title compound as a yellow oil.

Compound 168.3. Methyl 3-cyano-4-cyclobutylbenzoate

The title compound (2.60 g (95%), white solid) was prepared usingstandard chemical manipulations and a procedure similar to that used forthe preparation of compound 152.4 and using compound 168.2 (4.00 g, 12.7mmol) in place of compound 152.3.

Compound 168.4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using 168.3 in place of 152.4. m/z(ES+) 458 (M+H)⁺.

Compound 169.4-(1-(4-Cyclobutyl-3-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using 168.3 in place of 152.4. m/z(ES+) 440 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.88 (d, 2H), 7.67-7.50 (m,3H), 7.47 (d, 2H), 4.89-4.75 (m, 1H), 4.25-3.73 (m, 2H), 3.35-3.25 (m,1H), 3.16-2.75 (m, 4H), 2.30-1.94 (m, 6H), 1.93-1.56 (m, 4H), 1.51-1.32(m, 3H).

Compound 170.4-(1-(4-Cyclobutyl-3-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor preparation of compound 152 and using compounds 168.3 and 11.2HClsalt in place of compounds 152.4 and 1.5 respectively. m/z (ES+) 444(M+H)⁺.

Compound 171.4-(1-(4-Cyclobutyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor preparation of compounds 152 and 156 and using 168.3 in place of152.4. m/z (ES+) 488 (M+H)⁺.

Compound 172.1. (S)-Tetrahydrofuran-2-carbohydrazide

To a round-bottom flask was added a solution of(S)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) indichloromethane (40 mL). EDC.HCl (7.50 g, 39.1 mmol, 1.50 equiv), HOBT(5.20 g, 38.5 mmol, 1.50 equiv), and hydrazine hydrate (2 mL, 2.00equiv, 99%) were added to the reaction. The resulting solution wasstirred overnight at room temperature. The solids were removed byfiltration and the filtrate was concentrated in vacuo to furnish 5.38 g(80%) of the title compound as a yellow oil.

Compound 172.(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using (S)-tetrahydrofuran-2-carbohydrazide (compound172.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)⁺.

Compound 173.(S)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor the preparation of compound 172 and using compound 11.2HCl salt inplace of compound 1.5. m/z (ES+) 514 (M+H)⁺.

Compound 174.1. (R)-Tetrahydrofuran-2-carbohydrazide

To a round-bottom flask was added a solution of(R)-tetrahydrofuran-2-carboxylic acid (3.00 g, 25.8 mmol, 1.00 equiv) indichloromethane (60 mL). EDC.HCl (7.37 g, 38.5 mmol, 1.50 equiv), HOBt(5.24 g, 38.8 mmol, 1.50 equiv), and hydrazine hydrate (2.60 g, 51.9mmol, 2.00 equiv) were added to the reaction. The resulting solution wasstirred overnight at 25° C. The solids were removed with filtration. Thefiltrate was concentrated in vacuo to yield 2.00 g (59%) of(R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.

Compound 174.(R)-4-(1-(4-Cyclobutyl-2-methyl-5-(5-(tetrahydrofuran-2-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 152), using (R)-tetrahydrofuran-2-carbohydrazide (compound174.1) in place of acetohydrazide. m/z (ES+) 496 (M+H)⁺. ¹H NMR (300MHz, CD₃OD) δ 7.70 (d, 2H), 7.49-7.41 (m, 4H), 5.15 (t, 1H), 4.89-4.80(m, 1H), 4.14-3.92 (m, 3H), 3.65-3.51 (m, 1H), 3.33-3.27 (m, 1H),3.03-2.95 (m, 2H), 2.47-2.37 (m, 4H), 2.24-1.91 (m, 9H), 1.83-1.71 (m,4H).

Compound 175.1.4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid

The title compound was synthesized using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 and using bromo(cyclopentyl)magnesium in place ofbromo(cyclobutyl)magnesium.

Compound 175.4-(1-(4-Cyclopentyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was synthesized using a procedure similar to thatused for the preparation of compound 152 and using compound 175.1 inplace of compound 152.8. m/z (ES+) 495 (M+H)⁺.

Compound 176.1. tert-Butyl4-(4-bromophenyl)-4-hydroxy-2-methylpiperidine-1-carboxylate

The title compound was synthesized using a procedure similar to thatused for the preparation of compound 1.1 and using tert-butyl2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl4-oxopiperidine-1-carboxylate.

Compound 176.2. tert-Butyl4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate

The title compound was synthesized using procedures similar to thoseused for the preparation of compound 1.4 and using compound 176.1 inplace of compound 1.1.

Compound 176.3. 4-(2-Methylpiperidin-4-yl)benzonitrile

To a solution of tert-butyl4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate (compound 176.2, 500mg, 1.50 mmol, 1.00 equiv, 90%) in dichloromethane (3 mL) was added TFAdropwise (1 mL). The resulting mixture was stirred for 1.5 h at roomtemperature, then diluted with 30 mL of dichloromethane. The resultingmixture was washed with sodium bicarbonate (aq., 1 M. Note: significantgas evolution). The aqueous phase was extracted with 2×50 mL ofdichloromethane and the combined organic layers were dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with methanol/dichloromethane (1:50-1:20) as eluent toyield 280 mg (93%) of 4-(2-methylpiperidin-4-yl)benzonitrile as acolorless oil.

Compound 176.4. tert-Butyl4-(4-cyanophenyl)-2-methylpiperidine-1-carboxylate

The title compound was synthesized using a procedure similar to thatused for the preparation of compound 152.8 and using compound 164.1 inplace of compound 152.7.

Compound 176.4-(1-(4-Cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-2-methylpiperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-(2-methylpiperidin-4-yl)benzonitrile (compound 176.3, 210 mg, 0.940mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL). EDC.HCl (404 mg,2.11 mmol, 2.00 equiv), 4-dimethylaminopyridine (257 mg, 2.10 mmol, 2.00equiv), and4-cyclobutyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 176.4, 300 mg, 1.05 mmol, 1.00 equiv) were added to thereaction mixture. The resulting solution was stirred for 4 h at 25° C.,then diluted with 50 mL of ethyl acetate. The resulting mixture waswashed with 2×30 mL of NH₄Cl(aq., sat.) and 2×30 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. The residue waspurified using silica gel column chromatography withdichloromethane/methanol (20:1) as eluent. The crude product (˜20 mg)was further purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (48% CH₃CN up to 49% in 8min, up to 100% in 3 min, down to 48% in 2 min); Detector, Waters 2489254&220 nm. The fractions containing pure compound were combined andlyophilized to yield 3.8 mg (1%) of the title compound as a white solid.m/z (ES+) 468 (M+H)⁺.

Compound 177.1. 4-Chloro-5-iodo-2-methylbenzoic acid

To a round-bottom flask was added a solution of 4-chloro-2-methylbenzoicacid (30.0 g, 176 mmol, 1.00 equiv) in acetic acid (300 mL). NaIO₄ (19.0g, 88.8 mmol, 0.50 equiv), I₂ (49.0 g, 193 mmol, 1.10 equiv), andsulfuric acid (3 mL) were added to the reaction. The resulting mixturewas stirred overnight at 110° C. After cooling to ambient temperature,the reaction was carefully quenched with 500 mL of Na₂S₂O₃ (aq., sat.).The resulting solids were collected by filtration and then dissolved in500 mL of ethyl acetate. The organic phase was washed with 2×200 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. This resulted in 20.0 g (38%) of4-chloro-5-iodo-2-methylbenzoic acid as a white solid.

Compound 177.2. Methyl 4-chloro-5-iodo-2-methylbenzoate

To a solution of 4-chloro-5-iodo-2-methylbenzoic acid (compound 177.1,20.0 g, 67.5 mmol, 1.00 equiv) in methanol (100 mL) was added sulfuricacid (5 mL) dropwise. The resulting mixture was stirred overnight at 75°C. After cooling to ambient temperature, the methanol was removed underreduced pressure. The pH value of the remaining aqueous layer wascarefully adjusted to 7 with sodium bicarbonate (aq., 1 M. Note:significant gas evolution). The aqueous phase was extracted with 2×200mL of ethyl acetate and the combined organic layers were washed with2×100 mL of brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:50) as eluent tofurnish 20.0 g (95%) of methyl 4-chloro-5-iodo-2-methylbenzoate as alight yellow liquid.

Compound 177.3.4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 but using compounds 177.2 and 143.1 instead of compound 152.3 andacetoydrazide respectively.

Compound 177.4-(1-(4-Chloro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152but using compound 177.3 instead of compound 152.8. m/z (ES+) 464(M+H)⁺.

Compound 178.1. 2-Bromo-4-chlorobenzoate

The title compound (17.0 g light yellow solid, 80%) was prepared using aprocedure similar to that used for the preparation of compound 177.2 butusing 2-bromo-4-chlorobenzoic acid (20.0 g) in place of compound 177.1.

Compound 178.2. Methyl 4-chloro-2-ethylbenzoate

The title compound (2.20 g light colorless liquid, 55%) was preparedusing a procedure similar to that used for the preparation of compound48.1 but using compound 178.1 (5.00 g) in place of methyl2-bromo-4-methylbenzoate.

Compound 178.3.4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 using compound 178.2 and 3-methoxypropanehydrazide (compound143.1) instead of compound 152.2 and acetoydrazide respectively.

Compound 178.4-(1-(4-Chloro-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using a procedure similar to that usedfor the preparation of compound 152 but using compound 178.3 in place ofcompound 152.8. m/z (ES+) 478 (M+H)⁺.

Compound 179.4-(1-(4-Chloro-2-ethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 38and 178. m/z (ES+) 490 (M+H)⁺.

Compound 180.1. Methyl 4-bromo-2-fluorobenzoate

To a 500-mL three neck round-bottom flask was added a solution of4-bromo-2-fluorobenzoic acid (30.0 g, 137 mmol, 1.00 equiv) in methanol(200 mL). SOCl₂ (24.0 g, 202 mmol, 1.50 equiv) was added dropwise at 0°C. The resulting solution was stirred for 10 min at 0° C., for 30 min at25° C., and then for 3 h at 50° C. After cooling to room temperature,the resulting mixture was concentrated under reduced pressure. Theresidue was partitioned between water (100 mL) and ethyl acetate (100mL). The aqueous phase was extracted with 100 mL of ethyl acetate. Thecombined organic layers were washed with 1×100 mL of water, 1×100 mL ofsodium bicarbonate (aq. sat.) and 1×100 mL of brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to yield 30.0 g (94%) of the title compound as a light yellowsolid.

Compound 180.2. Methyl 4-ethyl-2-fluorobenzoate

The title compound (3.80 g light colorless oil, 97%) was prepared usinga procedure similar to that used for the preparation of compound 48.1but using compound 180.1 (5.00 g) in place of methyl2-bromo-4-methylbenzoate.

Compound 180.3.4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 using compounds 180.2 and 143.1 instead of compound 152.2 andacetoydrazide respectively.

Compound 180.4-(1-(4-Ethyl-2-fluoro-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 152but using compound 180.3 in place of compound 152.8. m/z (ES+) 462

(M+H)⁺.

Compound 181.1. 4-Bromo-2-ethylbenzoic acid

To a 1 L three neck round-bottom flask, which was purged and maintainedwith a nitrogen atmosphere, was added 4-bromo-2-fluorobenzoic acid (50.0g, 228 mmol, 1.00 equiv) in tetrahydrofuran (500 mL). A solution ofethylmagnesium bromide (250 mL, 3 M in THF) was added dropwise at 0° C.The resulting solution was stiffed for 3-4 h at 0° C. The mixture wasthen carefully quenched by dropwise addition of water at 0° C. Aftercomplete quench of the reaction, additional water was added and the pHwas adjusted to 2-3 with hydrogen chloride (aqueous, 2 M). The mixturewas extracted with 2×200 mL of ethyl acetate and the organic layers werecombined. Sodium hydroxide (2N, aq.) was employed to adjust the pH to7-8. The resulting mixture was washed with 2×200 mL of ethyl acetate.The pH value of the aqueous solution was adjusted to 2-3 with 2Nhydrogen chloride, then extracted with 2×200 mL of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. This resulted in 30.0 g (57%) of4-bromo-2-ethylbenzoic acid as a yellow solid.

Compound 181.2. Methyl 4-bromo-2-ethylbenzoate

The title compound (25.0 g light yellow liquid, 79%) was prepared usinga procedure similar to that used for the preparation of compound 177.2but using compound 181.1 (30.0 g) in place of compound 177.1.

Compound 181.3. Methyl 4-cyclobutyl-2-ethylbenzoate

To a stirred mixture of ZnBr₂ (33.5 g, 149 mmol, 4.00 equiv) in THF (350mL) under nitrogen at 0° C. was added dropwise a solution ofcyclobutylmagnesium bromide (148 mmol in 50 mL THF). After stirring at0° C. for 0.5 h, the temperature was lowered to −78° C. and Pd(dppf)Cl₂(2.00 g, 2.73 mmol, 0.07 equiv) was added followed by the addition of asolution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 9.00 g, 37.0mmol, 1.00 equiv) in tetrahydrofuran (10 mL) dropwise at the sametemperature. The reaction mixture was slowly allowed to reach ambienttemperature and then stirred overnight. The reaction was carefullyquenched with a saturated NH₄Cl aqueous solution (100 mL). The resultingmixture was extracted with 500 mL of ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:50) to furnish 8.00 g (99%) of the desiredproduct as a light yellow oil.

Compound 181.4. Methyl 4-cyclobutyl-2-ethyl-5-iodobenzoate

To a solution of methyl 4-cyclobutyl-2-ethylbenzoate (compound 181.3,7.70 g, 35.3 mmol, 1.00 equiv) in acetic acid (80 mL) was added iodine(8.98 g, 35.4 mmol, 1.00 equiv), NaIO₄ (3.78 g, 17.7 mmol, 0.50 equiv),and sulfuric acid (0.870 g, 8.87 mmol, 0.25 equiv). The reaction mixturewas stirred at 60° C. overnight. After cooling to room temperature, thereaction was slowly quenched with Na₂S₂O₃ (aq., sat.). The mixture wasextracted with 200 mL of ethyl acetate and the organic layer was driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel chromatography with ethyl acetate/petroleum ether(1:50) to furnish 10.5 g (86%) of the desired product as a colorlesssolid.

Compound 181.5. Methyl 5-cyano-4-cyclobutyl-2-ethylbenzoate

To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of methyl4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 5.50 g, 16.0 mmol,1.00 equiv) in N,N-dimethylformamide (150 mL). Zinc cyanide (2.78 g,23.7 mmol, 1.50 equiv) and Pd(PPh₃)₄ (1.83 g, 1.59 mmol, 0.10 equiv)were added to the reaction mixture. The resulting solution was stirredat 100° C. for 15 h under nitrogen. After cooling to ambienttemperature, the reaction was carefully quenched with 300 mL ofFeSO₄(aq., sat.) and diluted with ethyl acetate. The resulting mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water, and ethyl acetate. The layers were separated and theaqueous phase was extracted with 2×300 mL of ethyl acetate. The combinedorganic layers were washed with 2×300 mL of brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (1:100-1:50) as eluent to furnish 3.20 g (82%) of methyl5-cyano-4-cyclobutyl-2-ethylbenzoate as a light yellow oil.

Compound 181.6. Methyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate

To a round-bottom flask was added a solution of methyl5-cyano-4-cyclobutyl-2-ethylbenzoate (compound 181.5, 3.00 g, 12.3 mmol,1.00 equiv) in a solvent mixture of tetrahydrofuran and H₂O (80 mL/40mL). To this was added O,O′-diethyl dithiophosphate (6.69 g, 35.9 mmol,3.00 equiv) dropwise with stirring. The resulting solution was stiffedat 85° C. for 48 h (CAUTION: significant gas evolution occurs—this andall other reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, themixture was then concentrated in vacuo. The crude product was purifiedby re-crystallization from petroleum ether to furnish 1.30 g (38%) ofmethyl 5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate as a light yellowsolid.

Compound 181.7. Methyl4-cyclobutyl-2-ethyl-5-(imino(methylthio)methyl)benzoate

To a round-bottom flask was added a solution of methyl5-carbamothioyl-4-cyclobutyl-2-ethylbenzoate (compound 181.6, 1.50 g,5.41 mmol, 1.00 equiv) in tetrahydrofuran (30 mL). This was followed bythe addition of iodomethane (3.80 g, 26.8 mmol, 5.00 equiv) dropwisewith stirring. The resulting solution was stiffed at 25° C. for 15 h,then concentrated in vacuo. This resulted in 1.80 g (97%) of the titlecompound as a yellow oil.

Compound 181.8. Methyl4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate

To a round-bottom flask was added a solution of methyl4-cyclobutyl-2-ethyl-5-(methylsulfanyl)carboximidoylbenzoate (compound181.7, 900 mg, 3.09 mmol, 1.00 equiv) in AcOH (20 mL). Propionohydrazide(880 mg, 9.99 mmol, 3.00 equiv) was added and the resulting mixture wasstirred at 90° C. for 2 h. After cooling to ambient temperature, themixture was then concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:50-1:3) as eluent to give 0.360 g (37%) of the title compound as aclear oil.

Compound 181.9.4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid

To a round-bottom flask was added a solution of methyl4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoate (compound181.8, 360 mg, 1.15 mmol, 1.00 equiv) in methanol (20 mL). A solution ofsodium hydroxide (460 mg, 11.5 mmol, 10.0 equiv) in water (10 mL) wasadded to the reaction mixture. The resulting solution was stirred at 25°C. for 15 h. The organic solvent was then removed under reducedpressure. The pH value of the remaining aqueous phase was adjusted to2-3 with hydrogen chloride (aq., 2 M). The resulting precipitate wascollected by filtration and dried under high-vacuum to yield 320 mg(93%) of the title compound as a white solid.

Compound 181.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution of4-cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoic acid(compound 181.9, 160 mg, 0.530 mmol, 1.00 equiv) inN,N-dimethylformamide (20 mL) were added EDCI (113 mg, 0.590 mmol, 1.11equiv), DMAP (197 mg, 1.62 mmol, 3.03 equiv), and HOBT (87.5 mg, 0.650mmol, 1.21 equiv). After 5 min, 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 110 mg, 0.590 mmol, 1.10 equiv) was added.The resulting mixture was stirred at 25° C. for 15 h, then quenched with100 mL of ice water. The mixture was extracted with 2×150 mL of ethylacetate. The combined organic layers were washed with 3×150 mL of brine,dried over anhydrous sodium sulfate, and concentrated. The crude product(˜150 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (47% CH₃CN up to 61% in 6min, up to 100% in 1.5 min, down to 47% in 1.5 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 99.5 mg (40%) of the title compound as a whitesolid m/z (ES+) 468 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.71-7.69 (m,2H), 7.50-7.32 (m, 4H), 4.03-3.99 (m, 1H), 3.65-3.5 (m, 1H), 3.32-3.20(m, 1H), 2.90-2.95 (m, 4H), 2.70-2.74 (m, 2H), 2.20-1.98 (m, 6H),1.98-1.79 (m, 4H), 1.41 (t, 3H), 1.39-1.28 (m, 3H).

Compound 182.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 484 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d,2H), 7.49-7.37 (m, 3H), 7.11-7.05 (m, 1H), 4.89-4.80 (m, 1H), 3.81 (t,2H), 3.77-3.60 (m, 1H), 3.4 (s, 3H), 3.37-3.32 (m, 1H), 3.14 (t, 2H),3.15-2.9 (m, 2H), 2.92-2.5 (m, 2H), 2.39-2.36 (m, 1H), 2.02-1.85 (m,1H), 1.85-1.69 (m, 3H), 1.32-1.21 (m, 3H), 1.0-0.95 (m, 2H), 0.77-0.69(m, 2H).

Compound 183.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 470 (M+H)⁺.

Compound 184.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181 and using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 502 (M+H)⁺.

Compound 185.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 484 (M+H)⁺.

Compound 186.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-ethyl-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 181and using compound 11.2HCl salt in place of compound 1.5. m/z (ES+) 486(M+H)⁺.

Compound 187.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181 and using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 516 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.77 (d, 2H), 7.66-7.47(m, 2H), 7.47-7.35 (m, 2H), 4.89-4.83 (m, 1H), 4.08-4.03 (t, 1H), 3.79(t, 2H), 3.55 (t, 2H), 3.33 (s, 3H), 3.28-3.20 (m, 1H), 3.12 (t, 2H),2.80-2.68 (m, 2H), 2.27-1.68 (m, 10H), 1.27 (t, 3H).

Compound 188.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds143 and 181. m/z (ES+) 498 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d,2H), 7.44-7.31 (m, 4H), 4.89 (s, 1H), 4.04-3.98 (m, 1H), 3.79 (t, 2H),3.66-3.60 (m, 1H), 3.33 (s, 3H), 3.23-3.12 (m, 1H), 3.10 (t, 2H), 3.02(t, 2H), 2.77-2.66 (m, 2H), 2.19-2.04 (m, 6H), 1.80-1.68 (m, 4H),1.31-1.26 (m, 3H).

Compound 189.1. Methyl 4-(cyclobutylmethyl)-2-methylbenzoate

The title compound (4.00 g, yellow oil, 84%) was prepared using aprocedure similar to that used for the preparation of compound 181.3using compound 152.1 (5.00 g) and cyclobutylmethylmagnesium bromide inplace of compound 181.2 and cyclobutylmagnesium bromide respectively.

Compound 189.2. Methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate

To a round-bottom flask was added a solution of methyl4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.1, 8.40 g, 38.5mmol, 1.00 equiv) in AcOH (150 mL). NaIO₄ (5.00 g, 23.4 mmol, 0.50equiv), iodine (10.0 g, 39.4 mmol, 1.00 equiv), and sulfuric acid (0.3mL) were added to the reaction mixture. The resulting solution wasstirred at 60° C. for 12 h. After cooling to room temperature, thereaction was quenched with 200 mL of NaHSO₃ (aq). The mixture wasextracted with 2×200 mL of ethyl acetate, and the combined organiclayers were dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (20:1) as eluent to furnish 8.00 g(60%) of methyl 4-(cyclobutylmethyl)-5-iodo-2-methylbenzoate as a whitesolid.

Compound 189.3. methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate.

The title compound (5.0 g, light yellow oil, 88%) was prepared using aprocedure similar to that used for the preparation of compound 181.5using compound 189.2 (8.00 g) in place of compound 181.4.

Compound 189.4. Methyl5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate

To a round-bottom flask was added a solution of methyl5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00 g,20.6 mmol, 1.00 equiv) in a solvent mixture of THF and H₂O (50 mL/25mL). O,O′-diethyl dithiophosphate (15.0 g, 80.5 mmol, 4.00 equiv) wasadded to the reaction flask. The resulting solution was stirred at 80°C. for 48 h (CAUTION: significant gas evolution occurs—this and allother reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, thereaction was carefully quenched with 50 mL of brine. The mixture wasextracted with 3×50 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:4) as eluent to furnish 1.20 g (21%) of thetitle compound as a yellow oil.

Compound 189.5. Methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate

To a round-bottom flask was added a solution of methyl5-carbamothioyl-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.4,1.20 g, 4.33 mmol, 1.00 equiv) in tetrahydrofuran (25 mL). Iodomethane(5.00 g, 35.2 mmol, 8.00 equiv) was added to the reaction mixture. Theresulting solution was stirred at 20° C. for 12 h, and then concentratedin vacuo. This resulted in 1.10 g (87%) of methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate asa yellow oil.

Compound 189.6. Methyl4-(cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoate

To a round-bottom flask was added a solution of methyl4-(cyclobutylmethyl)-2-methyl-5-(methylsulfanyl)carboximidoylbenzoate(compound 189.5, 1.00 g, 3.43 mmol, 1.00 equiv) in AcOH (25 mL).Propionohydrazide (1.20 g, 13.6 mmol, 4.00 equiv) was added and theresulting mixture was stirred at 100° C. for 1 h. After cooling toambient temperature, the mixture was concentrated in vacuo. The residuewas purified using silica gel column chromatography with ethylacetate/petroleum ether (1:5) as eluent to furnish 300 mg (28%) of thetitle compound as a white solid.

Compound 189.7.4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

The title compound (260 mg, white solid, 91%) was prepared using aprocedure similar to that used for the preparation of compound 181.9using compound 189.6 (300 mg) in place of compound 181.8.

Compound 189.4-(1-(4-(Cyclobutylmethyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound (28 mg, white solid, 18%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 189.7 (100 mg) in place of compound 181.9. m/z (ES+) 468(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.67 (d, 2H), 7.52-7.47 (m, 3H), 7.26(s, 1H), 3.66-3.22 (m, 1H), 3.33-3.22 (m, 1H), 3.05-2.99 (m, 4H), 2.97(q, 2H), 2.53-2.47 (m, 1H), 2.47 and 2.45 (2 singlets, amide rotamers,ArCH₃, 3H) 2.00-1.50 (m, 10H), 1.41 (t, 3H).

Compound 190.1. Methyl 2-bromo-5-iodo-4-methylbenzoate

To a round-bottom flask was added a mixture of methyl2-bromo-4-methylbenzoate (2.00 g, 7.86 mmol, 1.00 equiv) in AcOH (20mL). I₂ (2.45 g, 9.65 mmol, 1.10 equiv), NaIO₄ (950 mg, 4.42 mmol, 0.50equiv), and sulfuric acid (0.1 mL, 0.15 equiv) were added and theresulting mixture was stirred at 100° C. overnight. After cooling toambient temperature, the reaction was carefully quenched with Na₂S₂O₃(aq., sat.). The resulting mixture was extracted with 2×50 mL of ethylacetate. The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo to yield 2.50 g (81%) of the title compound as anoff-white solid.

Compound 190.2. Methyl 2-bromo-5-cyano-4-methylbenzoate

The title compound (1.10 g, white solid, 61%) was prepared using aprocedure similar to that used for the preparation of compound 181.5using compound 190.1 (2.50 g) in place of compound 181.4.

Compound 190.3. Methyl 5-cyano-2-cyclopropyl-4-methylbenzoate

To a solution of methyl 2-bromo-5-cyano-4-methylbenzoate (compound190.2, 600 mg, 2.13 mmol, 1.00 equiv, 90%) in toluene (20 mL) undernitrogen were added cyclopropylboronic acid (552 mg, 6.43 mmol, 2.00equiv), a solution of potassium carbonate (876 mg, 6.34 mmol, 2.00equiv) in water (1 mL), Pd(dppf)Cl₂ (252 mg, 0.10 equiv), and Pd(OAc)₂(70 mg, 0.10 equiv). The resulting mixture was stirred under nitrogen at100° C. overnight. After cooling to ambient temperature, the mixture wasdiluted with 20 mL of H₂O, then extracted with 3×50 mL of ethyl acetate.The combined organic layers were dried (Na₂SO₄) and concentrated invacuo to furnish 450 mg (89%) of methyl5-cyano-2-cyclopropyl-4-methylbenzoate as a white solid.

Compound 190.4. Methyl 5-carbamothioyl-2-cyclopropyl-4-methylbenzoate.

To a round-bottom flask, was added a solution of methyl5-cyano-2-cyclopropyl-4-methylbenzoate (compound 190.3, 220 mg, 0.920mmol, 1.00 equiv, 90%) in tetrahydrofuran (6 mL). A solution ofO,O′-diethyl dithiophosphate (300 mg, 1.61 mmol, 2.00 equiv) in water(1.5 mL) was added to the solution, and the resulting mixture wasstirred overnight at 80° C. in an oil bath (CAUTION: significant gasevolution occurs—this and all other reactions described herein should becarried out in well ventilated fume hoods). After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (5:1) as eluent. The collected fractions werecombined and concentrated in vacuo to furnish 100 mg (39%) of methyl5-carbamothioyl-2-cyclopropyl-4-methylbenzoate as a yellow solid.

Compound 190.5. Methyl 2-cyclopropyl-4-methyl-5-(methylsulfanyl)carboximidoylbenzoate

To a solution of methyl 5-carbamothioyl-2-cyclopropyl-4-methylbenzoate(compound 190.4, 600 mg, 2.17 mmol, 1.00 equiv, 90%) in THF (55 mL) wasadded dropwise iodomethane (1 mL). The resulting mixture was stirredovernight at 25° C., then concentrated and dried under reduced pressureto yield 400 mg (56%) of the title compound as a yellow solid.

Compound 190.6. 2-Methoxyacetohydrazide

To a round-bottom flask, was added a solution of ethyl 2-methoxyacetate(10.0 g, 76.2 mmol, 1.00 equiv, 90%) and NH₂NH₂.H₂O (12 mL, 3.00 equiv)in ethanol (100 mL). The resulting solution was stirred for 3 h at 80°C. in an oil bath, then concentrated and dried under reduced pressure toyield 6 g (68%) of 2-methoxyacetohydrazide as a white solid.

Compound 190.7. Methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate

A solution of methyl2-cyclopropyl-4-methyl-5-(methylsulfanyl)carboximidoylbenzoate (compound190.5, 400 mg, 1.37 mmol, 1.00 equiv, 90%) and 2-methoxyacetohydrazide(compound 190.6, 889 mg, 7.69 mmol, 5.00 equiv) in AcOH (25 mL) wasstirred overnight at 90° C. After cooling to room temperature, themixture was concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether (2:1) aseluent. The collected fractions were combined and concentrated in vacuoto furnish 200 mg (44%) of methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoateas a white solid.

Compound 190.8.2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid

To a round-bottom flask was added a solution of methyl2-cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate(compound 190.7, 200 mg, 0.600 mmol, 1.00 equiv, 90%) in methanol (4mL). A solution of sodium hydroxide (106 mg, 2.65 mmol, 4.00 equiv) inwater (2 mL) was added to the reaction mixture. The resulting solutionwas stirred for 2 h at 60° C. After cooling to ambient temperature, theorganic solvent was removed under reduced pressure and the pH theremaining aqueous layer was adjusted to 2-3 with hydrogen chloride (aq,6 M). The resulting solids were collected by filtration and dried toyield 170 mg (89%) of the title compound as a white solid.

Compound 190.4-(1-(2-Cyclopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound (115.5 mg, white solid, 51%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 190.8 (150 mg) in place of compound 181.9. m/z (ES+) 456(M+H)⁺.

Compound 191.1.2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound190.8.

Compound 191.4-(1-(2-Ethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound (74.8 mg, white solid, 33%) was prepared using aprocedure similar to that used for the preparation of compound 181 usingcompound 191.1 (145 mg) in place of compound 181.9. m/z (ES+) 458(M+H)⁺.

Compound 192.4-(1-(2-Ethyl-4-methyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 470 (M+H)⁺.

Compound 193.4-(1-(2-Ethyl-5-(5-(1-methoxypropan-2-yl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 472 (M+H)⁺.

Compound 194.4-(1-(2-Ethyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound191. m/z (ES+) 444 (M+H)⁺.

Compound 195.4-(1-(2-Cyclobutyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound190. m/z (ES+) 470 (M+H)⁺.

Compound 196.1. Methyl 2-isopropyl-4-methylbenzoate

To a stiffed mixture of dibromozinc (39.0 g, 173 mmol, 4.00 equiv) inTHF (500 mL) under nitrogen at −48° C. was added dropwiseisopropylmagnesium bromide (3 M in THF, 170 mmol) over a period of 30min Pd(dppf)Cl₂ (0.5 g, 0.05 equiv) and methyl 2-bromo-4-methylbenzoate(10.0 g, 43.7 mmol, 1.00 equiv) were added to the above reactionmixture. After stirring for 1 h at −48° C., the reaction mixture wasquenched by the careful addition of 500 mL of NH₄Cl (aq.). The resultingmixture was extracted with 3×500 mL of ethyl acetate. The combinedorganic layers were washed with 3×500 mL of brine and concentrated invacuo. The residue was purified using silica gel column chromatographywith petroleum ether (1:1) as eluent. This resulted in 6.50 g (77%) ofmethyl 2-isopropyl-4-methylbenzoate as a yellow oil.

Compound 196.2. Methyl 5-iodo-2-isopropyl-4-methylbenzoate

To a round-bottom flask, was added a solution of methyl2-isopropyl-4-methylbenzoate (compound 196.1, 6.50 g, 33.8 mmol, 1.00equiv) in acetic acid (60 mL). Iodide (9.50 g, 37.4 mmol, 1.10 equiv),sodium periodate (3.60 g, 16.8 mmol, 0.50 equiv), and sulfuric acid(0.500 g, 0.15 equiv) were added to the reaction mixture. The resultingsolution was stirred overnight at 100° C. After cooling to roomtemperature, the reaction was quenched with Na₂S₂O₃ (aq., sat.). Themixture extracted with 3×100 mL of ethyl acetate. The combined organiclayers were washed with 3×100 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. This resulted in 6.00 g (56%) ofmethyl 5-iodo-2-isopropyl-4-methylbenzoate as a yellow oil.

Compound 196.3. Methyl 5-cyano-2-isopropyl-4-methylbenzoate

The title compound (0.8 g, white solid, 37%) was prepared using aprocedure similar to that used for the preparation of compound 181.5using compound 196.2 (3.20 g) in place of compound 181.4.

Compound 196.4. Methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate

To a round-bottom flask was added a solution of methyl5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol,1.00 equiv) in tetrahydrofuran/H₂O (10/5 mL). O,O′-diethyldithiophosphate (2.05 g, 11.0 mmol, 3.00 equiv) was added to thereaction mixture. The resulting solution was stirred for 15 h at 85° C.in an oil bath (CAUTION: significant gas evolution occurs—this and allother reactions described herein should be carried out in wellventilated fume hoods). After cooling to ambient temperature, themixture was extracted with 2×100 mL of ethyl acetate. The combinedorganic layers were dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800 g(86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a yellowoil.

Compound 196.5. Methyl5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate

The title compound (0.800 g, yellow oil, 92%) was prepared using aprocedure similar to that used for the preparation of compound 181.7using compound 196.4 (820 mg) in place of compound 181.6.

Compound 196.6. Methyl2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoate

A solution of methyl5-(imino(methylthio)methyl)-2-isopropyl-4-methylbenzoate (compound196.5, 800 mg, 3.01 mmol, 1.00 equiv) and 2-methoxyacetohydrazide(compound 190.6, 1.90 g, 18.3 mmol, 5.00 equiv) in acetic acid (30 mL)was stirred for 2 h at 80° C. in an oil bath, then concentrated invacuo. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (1:50-1:2) as eluent to yield 250 mg(27%) of methyl2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoateas a clear oil.

Compound 196.7.2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid

The title compound (0.20 g, white solid, 84%) was prepared using aprocedure similar to that used for the preparation of compound 181.9using compound 196.6 (250 mg) in place of compound 181.8.

Compound 196.4-(1-(2-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrileand Compound 197.4-(1-(5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methyl-2-propylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of2-isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-4-methylbenzoicacid (compound 196.7, 200 mg, 0.690 mmol, 1.00 equiv) in DMF (20 mL)were added EDCI (200 mg, 1.04 mmol, 1.51 equiv), DMAP (250 mg, 2.05mmol, 2.96 equiv), and HOBT (110 mg, 0.810 mmol, 1.18 equiv). Afterstiffing for 30 min at room temperature compound 1.5, 142 mg, 0.640mmol, 0.92 equiv was added and the resulting solution was stirred for 15h at 25° C., then quenched with 100 mL of ice water. The resultingmixture was extracted with 2×200 mL of ethyl acetate. The combinedorganic layers were washed with 2×100 mL of brine, then dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:50-1:1-1:0) as eluent. The crude product(−120 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (40.0% CH₃CN up to55.0% in 8 min, up to 100.0% in 1 min, down to 40.0% in 1 min);Detector, Waters 2489 254&220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 57.4 mg (18%) of compound 196 and11.7 mg (4%) of compound 197 as white solids. Compound 196. m/z (ES+)458 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.65-7.62 (m, 2H,), 7.55-7.28 (m,4H), 4.61 (s, 2H), 3.67-3.62 (m, 1H), 3.44 (s, 3H), 3.27-3.20 (m, 1H),3.04-2.86 (m, 3H), 2.51 (s, 3H), 1.99-1.68 (m, 5H), 1.31-1.26 (m, 6H).Compound 197. m/z (ES+) 458 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.66-7.63(m, 2H), 7.55 (s, 1H), 7.46-7.37 (m, 2H), 7.28 (m, 1H), 4.61 (s, 2H),3.62-3.58 (m, 1H), 3.44 (s, 3H), 3.19-3.05 (m, 2H), 3.04-2.91 (m, 2H),2.73-2.45 (m, 5H), 1.98-1.54 (m, 6H), 1.05-0.85 (m, 3H).

Compound 198.1. Methyl 4-isopropyl-2-methylbenzoate

A dried round bottom flask with stir bar was purged with nitrogen andcharged with diisopropyl zinc (25 mL of a 1 M solution in THF, 25 mmol,2.0 equiv). Methyl 4-bromo-2-methylbenzoate (compound 152.1, 2.86 g,12.5 mmol, 1.0 equiv) in 1,4-dioxane (25 mL) was added followed byaddition of Pd(dppf)₂Cl₂.DCM (1.02 g, 1.25 mmol, 0.1 equiv) (exothermicupon catalyst addition). The system was purged with additional nitrogenthen argon and heated to 100° C. for 4 hours then stirred at roomtemperature for 12 hours. The mixture was carefully quenched with 1M HCl(ag., 12 mL) (some bubbling) and then diluted with water (100 mL) andethyl acetate (150 mL) and mixed. The mixture was filtered throughcelite and washed with water and ethyl acetate (2×25 mL each). Thelayers were separated and the aqueous was extracted with addition ethylacetate (50 mL). The combined organics were washed with brine (50 mL),dried (Na₂SO₄), and concentrated under reduced pressure. The crudeproduct was purified by silica gel column chromatography (hexanes to 6%ethyl acetate) to obtain the title compound as a colorless oil (2.31 g,96%). ¹H NMR (400 MHz, CDCl₃): δ 7.86 (d with fine str, J=8.8 Hz, 1H),7.12-7.07 (m, 2H), 3.87 (s, 3H), 2.90 (septet, J=6.8 Hz, 1H), 2.59 (s,3H), 1.25 (d, J=6.8 Hz, 6H).

Compound 198.2. Methyl 5-iodo-4-isopropyl-2-methylbenzoate

To methyl 4-isopropyl-2-methylbenzoate (compound 198.1, 2.31 g, 12.0mmol, 1.0 equiv) in a 100 mL round bottom flask was carefully added TFA(24 mL) and the mixture was cooled to 0° C. N-Iodosuccinimide (2.70 g,12.0 mmol, 1.0 equi) was added portionwise over 2 minutes and theresulting mixture was added under nitrogen and stirred at 0° C. for 20min then at room temperature for 15 hours. The mixture was carefullydiluted. To a mixture of dichloromethane (50 mL) and added to saturatedaqueous disodium phosphate to maintain a pH above 3 (total disodiumphosphate about 500 mL). The mixture was shaken well, separated and theaqueous was extracted with additional DCM (5×25 mL). The combinedorganics was washed with a mix of saturated sodium sulfite (10 mL) pluswater (40 mL) followed by brine (50 mL), dried (Na₂SO₄), filtered andremoved in vacuo. The crude product was purified by silica columnchromatography (hexanes to 3% ethyl acetate) to obtain the titlecompound as a light tan oil (3.59 g, 94%). ¹H NMR (400 MHz, CDCl₃): δ8.35 (s, 1H), 7.08 (s, 1H), 3.87 (s, 3H), 3.17 (septet, J=6.8 Hz, 1H),2.59 (s, 3H), 1.23 (d, J=6.8 Hz, 6H).

Compound 198.3. Methyl 5-cyano-4-isopropyl-2-methylbenzoate

To a dried round bottom flask was added methyl5-iodo-4-isopropyl-2-methylbenzoate (compound 198.2, 2.00 g, 6.29 mmol,1.0 equiv), zinc cyanide (1.48 g, 12.6 mmol, 2.0 equiv), DMF (20 mL) andPd(PPh₃)₄ (364 mg, 0.315 mmol, 0.05 equiv). The system was purged withnitrogen followed by argon and the mixture was heated at 100° C. for 15hours. The reaction was allowed to cool to room temperature then dilutedwith ethyl acetate (50 mL) and quenched with 1 M FeSO₄ (25 mL). Themixture was stirred vigorously for 40 minutes then filtered throughcelite and washed with 1 M FeSO₄ (15 mL), water (50 mL) and ethylacetate (150 mL). The layers were separated and the aqueous phase wasextracted with ethyl acetate (50 mL). The combined organic layers werewashed with brine (4×100 mL), dried (Na₂SO₄), filtered, and concentratedin vacuo. The product was purified by silica column chromatography(hexanes to 8% ethyl acetate) to obtain the title compound (1.14 g,83%). ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 7.25 (s, 1H), 3.91 (s,3H), 3.37 (septet, J=6.8 Hz, 1H), 2.67 (s, 3H), 1.32 (d, J=6.8 Hz, 6H).

Compound 198.4. Methyl5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate.

Methyl 5-cyano-4-isopropyl-2-methylbenzoate (compound 198.3, 1.12 g,5.16 mmol, 1.0 equiv), O,O′-diethyl dithiophosphate (90%) (2.0 mL, 10.7mmol, 2.1 equiv) and water (200 μL) were added to a 16 mL vial and themixture was heated with the cap loose at 80° C. for 85 hours (CAUTION:significant gas evolution occurs—this and all other reactions describedherein should be carried out in well ventilated fume hoods). Note thatadditional O,O′-diethyl dithiophosphate (0.5 mL, 2.7 mmol, 0.5 equiv)and water (50 μL) was added at 6 hours and 14 hours. The intermediatethioamide is also observed by LC/MS during the reaction and is heateduntil the conversion to the desired product is complete. The reactionmixture was diluted with ethyl acetate (75 mL) and washed with saturatedaqueous NaHCO₃ (20 mL) followed by 1 M NaH₂PO₄ (10 mL) and brine (10mL). The organics were dried (Na₂SO₄), filtered and removed in vacuo.The crude product was purified by silica column chromatography (hexanesto 25% ethyl acetate) to obtain a colorless oil (1.12 g, 78%). m/z (ES+)280 (M+H)⁺.

Compound 198.5. Methyl4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate

Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate(compound 198.4, 33 mg, 0.12 mmol, 1.0 equiv), 3-methoxypropanehydrazide(compound 143.1, 21 mg, 0.18 mmol, 1.5 equiv) and acetic acid (1.2 mL)were added to a 4-mL vial and heated at 80° C. with a loose cap for 4hours. The solvent was removed in vacuo and the residue was dissolved inDCM (10 mL) and washed with saturated NaHCO₃ (5 mL) then brine (5 mL),dried (Na₂SO₄), filtered and evaporated to a colorless oil (theoreticalyield). m/z (ES+) 318 (M+H)⁺.

Compound 198.6.4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

To crude methyl4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate(compound 198.5, 0.12 mmol, 1.0 equiv) from the previous step in a 4-mLvial was added lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0equiv), methanol (0.9 mL) and water (0.3 mL). The resulting mixture wasstiffed at room temperature for 3 hours followed by 50° C. for 3 hoursand 40° C. for 17 hours. The solvents were removed in vacuo and theresidue was diluted with water (7 mL) plus saturated NaHCO₃ (1 mL) andthe aqueous was washed with diethyl ether (2 mL). The organic was backextracted with a mix of water (2 mL) plus saturated NaHCO₃ (0.5 mL). Thecombined aqueous was acidified to pH=3 with 1 M H₃PO₄ and extracted withdichlormethane (3×5 mL). The organics were dried (Na₂SO₄), filtered andremoved in vacuo to obtain the title compound as a white waxy solid(31.5 mg, 88% over 2 steps). m/z (ES+) 304 (M+H)⁺.

Compound 198.4-(1-(4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a 4-mL vial was added4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 198.6, 31 mg, 0.10 mmol, 1.0 equiv),4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 23 mg, 0.10mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (22 mg,0.13 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (21.5 mg, 0.11 mmol, 1.1 equiv), DMF (1 mL) and DIEA (71μL, 0.41 mmol, 4 equiv). The mixture was stirred at room temperature for24 hours then diluted with ethyl acetate (10 mL) and washed with brine(10 mL). The aqueous was back extracted with ethyl acetate (3 mL) andthe combined organics was washed with saturated NaHCO₃ (5 mL), 1 MNaH₂PO₄ (5 mL), and brine (5 mL). The organics were dried (Na₂SO₄),filtered and removed in vacuo. The crude residue was purified bypreparative TLC (DCM/8% MeOH) to obtain the title compound as an offwhite solid (23 mg, 48%). m/z (ES+) 472 (M+H)⁺.

Compound 199.4-(1-(4-Isopropyl-5-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 458 (M+H)⁺.

Compound 200.4-(1-(4-Isopropyl-3-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 458 (M+H)⁺.

Compound 201.4-(1-(4-Isopropyl-3-(5-(methoxymethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 198). m/z (ES+) 444 (M+H)⁺.

Compound 202.1. Methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate

To an 8-mL vial was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate(152.4, 100 mg, 0.436 mmol, 1.0 equiv), potassium carbonate (181 mg,1.31 mmol, 3.0 equiv) and DMSO (2.2 mL) and stirring was initiated.Hydrogen peroxide (50 wt %) (176 μL, 3.05 mmol, 7.0 equiv) was addedover about 1 minute. The mixture was stirred at room temperature for 29hours then diluted into brine (10 mL) plus 1 M H₃PO₄ (1.5 mL). Themixture was extracted with ethyl acetate (10 mL×1, 3 mL×1). The combinedorganic layers were washed with brine (10 mL) plus a few drops of 1 MH₃PO₄ followed by a mixture of water (10 mL) plus saturated NaHCO₃ (1mL) and finally brine (5 mL). The organics was dried (Na₂SO₄), filteredand evaporated to obtain the title compound as a white solid (59 mg,55%). m/z (ES+) 248.0 (M+H)⁺.

Compound 202.2. Methyl4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate

To a vial was added methyl 5-carbamoyl-4-cyclobutyl-2-methylbenzoate(compound 202.1, 59 mg, 0.24 mmol, 1.0 equiv) and N,N-dimethylformamidedimethyl acetal (1 mL) was added. The mixture was heated at 80° C. for 5hours then the solvents were removed in vacuo. To the residue was addedacetic acid (400 μL) and a solution of anhydrous hydrazine (8.2 μL, 0.26mmol, 1.1 equiv) in acetic acid (100.4). To the resulting thicksuspension was added additional acetic acid (500 μL) and the mixture wasstirred at 80° C. for 1.5 hours then the solvents removed in vacuo.Ethyl acetate (5 mL) and DCM (5 mL) was added (some undissolved solids).The organics was washed with saturated NaHCO₃ (10 mL) and brine (5 mL)and removed in vacuo to obtain the title compound as a white solid(theoretical yield). m/z (ES+) 272 (M+H)⁺.

Compound 202.3. 4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoicacid

To crude methyl 4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoate(compound 202.2, 0.24 mmol, 1.0 equiv) from the previous step in a 4-mLvial was added methanol (1.5 mL) and water (0.5 mL) and lithiumhydroxide monohydrate (20 mg, 0.48 mmol, 2.0 equiv), The resultingmixture was stirred at 40° C. for 42 hours. The reaction mixture wasdiluted into water (5 mL), acidified to pH 3 with 1M H₃PO₄ and extractedwith DCM (3×5 mL). The organics were dried (Na₂SO₄), filtered andconcentrated in vacuo to obtain the title compound as a white solid (61mg, 98% over 2 steps). m/z (ES+) 258 (M+H)⁺.

Compound 202.4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a 4-mL vial was added4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound202.3, 31 mg, 0.12 mmol, 1.0 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 27 mg, 0.12 mmol, 1.0 equiv),1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15 mmol, 1.25equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83 μL, 0.48 mmol, 4equiv). The mixture was stirred at room temperature for 4 hours thendiluted with ethyl acetate (10 mL) and washed with 1 M NaH₂PO₄ (5 mL).The aqueous was back extracted with ethyl acetate (3 mL) and thecombined organics was washed with brine (5 mL), saturated NaHCO₃ (5 mL)and brine (5 mL). The organics were dried (Na₂SO₄), filtered and removedin vacuo. The crude residue was purified by preparative TLC (DCM/8%MeOH) to obtain the title compound as a white solid (23 mg, 46%). m/z(ES+) 426 (M+H)⁺.

Compound 203.4-(1-(4-Cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

To a 4-mL vial was added4-cyclobutyl-2-methyl-5-(4H-1,2,4-triazol-3-yl)benzoic acid (compound202.3, 31 mg, 0.12 mmol, 1.0 equiv),4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 31 mg, 0.13 mmol,1.1 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (25 mg, 0.15mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (25 mg, 0.13 mmol, 1.1 equiv), DMF (0.6 mL) and DIEA (83μL, 0.48 mmol, 4 equiv). The mixture was stiffed at room temperature for4 hours then diluted with ethyl acetate (10 mL) and washed with 1 MNaH₂PO₄ (5 mL). The aqueous was back extracted with ethyl acetate (3 mL)and the combined organics was washed with brine (5 mL), saturated NaHCO₃(5 mL) and brine (5 mL). The organics were dried (Na₂SO₄), filtered andremoved in vacuo. The crude residue was purified by preparative TLC(DCM/8% MeOH) to obtain the title compound as a white solid (30 mg,56%). m/z (ES+) 444 (M+H)⁺.

Compound 204.1. Methyl 2,4-dibromobenzoate

A solution of 2,4-dibromobenzoic acid (52.0 g, 176 mmol, 1.00 equiv,95%) and sulfuric acid (20 mL) in methanol (400 mL) was stirred at 90°C. overnight. After cooling to room temperature, the mixture wasconcentrated under reduced pressure. The residue was diluted with 500 mLof ethyl acetate and washed with 3×100 mL of H₂O followed by 1×100 mL ofNaHCO₃ (aq., sat. Note: gas evolution occurs). The organic layer wasdried over anhydrous sodium sulfate and concentrated in vacuo. Thisresulted in 45.0 g (78%) of methyl 2,4-dibromobenzoate as a yellow oil.

Compound 204.2. Methyl 2,4-diethylbenzoate

To stirred mixture of ZnBr₂ (40.0 g, 176 mmol, 5.44 equiv, 99%) in THF(100 mL) under nitrogen at 0° C. was added dropwise EtMgBr (60 mL, 3 Min THF). After 0.5 h at 0° C., the temperature was lowered to −78° C.and PdCl₂(dppf) (3.72 g, 5.03 mmol, 0.16 equiv, 99%) was added followedby the dropwise addition of a solution of methyl 2,4-dibromobenzoate(compound 204.1, 10.0 g, 32.3 mmol, 1.00 equiv, 95%) in THF (200 mL).The reaction was stirred overnight at room temperature, then carefullyquenched with water followed by HCl (aq., 1 M). The resulting mixturewas extracted with 3×500 mL of ethyl acetate, and the combined organiclayers were washed with 3×50 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:60) as eluent to furnish 6.30 g (96%) of methyl 2,4-diethylbenzoateas a colorless oil

Compound 204.3. Methyl 2,4-diethyl-5-iodobenzoate

The title compound (4.0 g, light yellow oil, 69%) was prepared using aprocedure similar to that used for the preparation of compound 181.4using compound 204.2 (3.50 g) in place of compound 181.3.

Compound 204.4. 2,4-Diethyl-5-iodobenzoic acid

The title compound (3.24 g, white solid, 85%) was prepared using aprocedure similar to that used for the preparation of compound 181.9using compound 204.3 (4.00 g) in place of compound 181.8.

Compound 204.5. 2,4-Diethyl-5-(methoxycarbonyl)benzoic acid

To a stiffed solution of 2,4-diethyl-5-iodobenzoic acid (compound204.4., 500 mg, 1.64 mmol, 1.00 equiv, 90%) in tetrahydrofuran (20 mL)at −78° C. under nitrogen was added dropwise a solution of n-BuLi (1.73mL, 4.10 mmol, 2.36 M in THF). After 5 minutes, a solution of methylchloroformate (0.315 mL, 4.10 mmol, 2.50 equiv) in THF (5 mL) was addeddropwise to the reaction at −78° C. over 5 minutes. The reaction wasstirred for another 5 min at −78° C., and then carefully quenched with10 mL of water. The pH was adjusted to 1-2 with hydrochloric acid (6 M)and the resulting mixture was extracted with ethyl acetate (2×30 mL).The combined organic layers were washed with 20 mL of brine, then driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by silica gel column chromatograph with ethylacetate-petroleum ether (1:20) as eluent to yield 96 mg (25%) of thetitle compound as an off-white solid.

Compound 204.6. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzoate

To a round-bottom flask, were added a solution of2,4-diethyl-5-(methoxycarbonyl)benzoic acid (compound 204.5, 500 mg,2.12 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 470 mg, 2.12 mmol, 1 equiv), EDC.HCl (810 mg, 4.24 mmol,2.00 equiv), and 4-dimethylaminopyridine (520 mg, 4.24 mmol, 2 equiv) inN,N-dimethylformamide (15 mL). The reaction was stirred overnight at 25°C. Upon reaction completion, the reaction mixture was diluted with 30 mLof ethyl acetate, then washed with 1×20 mL of NH₄Cl (aq.) and 1×20 mL ofbrine. The organic phase was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by silica gelchromatography with a solvent mixture of ethyl acetate and petroleumether (1:1) to yield 500 mg (60%) of the title compound as a pale yellowsolid.

Compound 204.7.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide

To a solution of compound 204.6 (500 mg, 1.05 mmol, 1.00 equiv, 85%) inethanol (6 mL) was added hydrazine hydrate (3 mL). The resultingsolution was stirred overnight at 90° C. After cooling to ambienttemperature, the mixture was concentrated in vacuo. The residue wasdiluted with 20 mL of ethyl acetate, then washed with 1×5 mL of brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography withdichloromethane-methanol (20:1) as eluent to yield 260 mg (55%) of thedesired compound as a yellow solid.

Compound 204.8.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide(compound 204.7, 100 mg, 0.220 mmol, 1.00 equiv, 90%) in a solventmixture of water (2 mL) and dioxane (3 mL). Sodium bicarbonate (62 mg,0.740 mmol, 3.00 equiv) was added to the reaction mixture at roomtemperature, and stirred for 5 minutes. BrCN (75 mg, 0.740 mmol, 3.00equiv) was then added to the reaction at room temperature. The resultingsolution was stirred for 2 h at room temperature, then quenched with 30mL of FeSO₄(aq., sat.) and diluted with ethyl acetate. The resultingmixture was stirred vigorously then filtered through celite and washedwith 1 M FeSO₄, water, and ethyl acetate. The layers were separated andthe aqueous phase was extracted with 2×50 mL of ethyl acetate. Thecombined organic layers were washed with 2×50 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. This resulted in100 mg (89%) of the title compound as a yellow solid. The compound wasused in the next step reaction without further purification.

Compound 204.9.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide

A mixture of compound 204.8 (100 mg, 0.200 mmol, 1.00 equiv, 85%) andpotassium hydroxide (132 mg, 2.35 mmol, 10.0 equiv) in ethanol (10 mL)was stirred at 85° C. overnight. After cooling to ambient temperature,the pH was adjusted to 7 with acetic acid and the resulting solution wasconcentrated in vacuo. The residue was diluted with 50 mL of ethylacetate, washed with 2×20 mL of brine, then concentrated in vacuo. Thecrude product was dried in a vacuum oven, before it was charged onto asilica gel column, and purified with dichloromethane-methanol (20:1) toafford 100 mg (85%) of the title compound as a yellow solid.

Compound 204.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzamide(compound 204.9, 100 mg, 0.170 mmol, 1.00 equiv) in dichloromethane (10mL). Triethylamine (170 mg, 1.68 mmol, 8.00 equiv) was added to thereaction at room temperature, followed by dropwise addition of asolution of (CF₃CO)₂O (160 mg, 0.760 mmol, 4.50 equiv) indichloromethane (0.5 mL) at 0 to 5° C. The resulting solution wasstirred at room temperature for another 2 hours. The mixture was dilutedwith 60 mL of ethyl acetate, then washed with 3×20 mL of brine. Theorganic layer was dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified by prep-HPLC (SunFire Prep C18,19*150 mm 5 um, water with 0.05% TFA and CH₃CN (53.0% CH₃CN up to 65.0%in 8 min, up to 100.0% in 2 min, down to 53.0% in 1 min). The fractionscontaining pure compound were combined and lyophilized to yield 50 mg(50%) of the title compound as a white solid. m/z (ES+) 458 (M+H)⁺. ¹HNMR (300 MHz, CD₃OD): δ 7.63 (d, 2H), 7.45-7.30 (m, 4H), 4.89-4.80 (m,1H, overlapped), 4.36 (q, 2H), 3.60-3.57 (m, 1H), 3.29-3.23 (m, 1H),3.19-2.85 (m, 4H), 2.74-2.56 (m, 2H), 2.00-1.82 (m, 1H), 1.77-1.66 (m,3H), 1.40 (t, 3H), 1.30-1.21 (m, 3H), 1.11 (t, 3H).

Compound 205.4-(1-(5-(5-Ethoxy-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 430 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69(d, 2H), 7.52-7.47 (m, 3H), 7.29 (s, 1H), 4.89-4.80 (m, 1H, overlapped),4.42-4.40 (m, 2H), 3.64-3.61 (m, 1H), 3.02-2.96 (m, 2H), 2.51 (s, 3H),2.41 and 2.31 (2 singlets, amide rotamers, ArCH₃, 3H), 2.05-2.02 (m,1H), 1.77-1.46 (m, 3H), 1.45 (t, 3H).

Compound 206.4-(1-(5-(5-(2-Methoxyethoxy)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation4-(I-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 460 (M+H)⁺.

Compound 207.4-(1-(2,4-Dimethyl-5-(5-((tetrahydrofuran-3-yl)oxy)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204). m/z (ES+) 472 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69(d, J=6.0 Hz, 2H), 7.58-7.37 (m, 3H), 7.30 (br s, 1H), 5.40 (br s, 1H),˜4.9 (1H partially obscured by water peak), 4.08-3.96 (m, 3H), 3.96-3.88(m, 1H), 3.71-3.58 (m, 1H), 3.33-3.22 (m, 1H), 3.00 (t with finestructure, J=9.0 Hz, 2H), 2.52 (s, 3H), 2.42 & 2.32 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.38-2.20 (m, 2H), 2.08-1.97 (m, 1H), 1.93-1.55(m, 3H).

Compound 208.4-(1-(2,4-Diethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-(I-(5-(5-amino-1,3,4-oxadiazol-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile(compound 204.8, 80.0 mg, 0.150 mmol, 1.00 equiv, 80%) and potassiumhydroxide (104 mg, 1.85 mmol, 10.00 equiv) in methanol (10 mL). Theresulting mixture was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was purified using silica gel columnchromatography with dichloromethane/methanol (20:1) as eluent. The crudeproduct (50 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (40% CH₃CN up to64% in 8 min, up to 100% in 1 min, down to 40% in 1 min); Detector,Waters 2489 254&220 nm. The fractions containing pure compound werecombined and lyophilized to yield 1.7 mg (3%) of the title compound as awhite solid. m/z (ES+) 444 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.63 (d,J=5.7 Hz, 2H), 7.45-7.30 (m, 4H), 4.85-4.80 (m, 1H), 4.02 (s, 3H),3.65-3.62 (m, 1H), 3.15-3.10 (m, 1H), 2.90-2.84 (m, 4H), 2.72-2.60 (m,2H), 2.02-2.00 (m, 1H), 1.72-1.65 (m, 3H), 1.30-1.25 (m, 3H), 1.11 (t,3H).

Compound 209.1.2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound198.6), but using methyl 2,4-diethyl-5-iodobenzoate (compound 204.3)instead compound 198.2 as the starting material.

Compound 209.4-(1-(2,4-Diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid(compound 209.1, 300 mg, 0.940 mmol, 1.00 equiv, 95%) inN,N-dimethylformamide (20 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 243 mg, 1.09 mmol, 1.10 equiv), EDC.HCl(380 mg, 1.98 mmol, 2.00 equiv), and 4-dimethylaminopyridine (240 mg,1.96 mmol, 2.09 equiv) were added to the reaction mixture. The resultingsolution was stirred overnight at room temperature, then diluted with100 mL of ethyl acetate. The organic layer was washed with 3×15 mL ofbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was purified using silica gel column chromatography withethyl acetate as eluent. The crude product (300 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (35% CH₃CN up to 60% in 8 min, up to 100% in 1 min, downto 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 188 mg(42%) of the title compound as a white solid. m/z (ES+) 472 (M+H)⁺.

Compound 210.4-(1-(2,4-Diethyl-5-(5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 209) but using tetrahydrofuran-3-carbohydrazide (compound38.2) instead of 3-methoxypropanehydrazide (compound 143.1). m/z (ES+)484.05 (M+H)⁺.

Compound 211.2. Methyl 2-ethyl-5-iodo-4-methylbenzoate

To a round-bottom flask was added a solution of methyl2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00 equiv)in AcOH (100 mL). NaIO₄ (7.51 g, 35.1 mmol, 0.50 equiv) and I₂ (21.4 g,84.3 mmol, 1.20 equiv) were added in portions at 25° C. Sulfuric acid(1.60 g, 16.3 mmol, 0.20 equiv) was then added to the reaction mixturedropwise at 25° C. The resulting solution was stirred for 12 h at 110°C. in an oil bath, and then cooled to ambient temperature. The reactionwas quenched with 150 mL of Na₂S₂O₃ (aq., sat.). The aqueous phase wasextracted with 2×200 mL of ethyl acetate. The combined organic layerswere washed with 3×300 mL of sodium bicarbonate (aq.) and 1×150 mL ofbrine. The mixture was dried over anhydrous sodium sulfate andconcentrated in vacuo. This resulted in 20.0 g (94%) of methyl2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.

Compound 211.3. 2-Ethyl-5-iodo-4-methylbenzoic acid

To a round-bottom flask, was added a solution of methyl2-ethyl-5-iodo-4-methylbenzoate (compound 211.2, 10.0 g, 32.9 mmol, 1.00equiv) in methanol (40 mL). A solution of NaOH (5.26 g, 132 mmol, 4.00equiv) in water (20 mL) was added dropwise. After stirring for 12 h at40° C., the organic solvent was removed under reduced pressure. The pHof the remaining aqueous phase was adjusted to 4 with hydrogen chloride(aq., 6 M), then extracted with 2×100 mL of ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedin vacuo. This resulted in 9.30 g (97%) of2-ethyl-5-iodo-4-methylbenzoic acid as a white solid.

Compound 211.4. 2-Ethyl-5-formyl-4-methylbenzoic acid

To a stirred solution of 2-ethyl-5-iodo-4-methylbenzoic acid (compound211.3, 5.00 g, 17.2 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) at−78° C. under nitrogen was added dropwise n-BuLi (17 mL, 2 M in THF,2.00 equiv). After 1 h at −78° C., DMF (7.00 g, 95.8 mmol, 3.00 equiv)was added dropwise at −78° C. The resulting solution was slowly warmedup to 25° C., then carefully quenched with water followed by theaddition of 10 mL of HCl (aq., 6 M). The aqueous phase was extractedwith 3×100 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (2:1) as eluent to furnish 450 mg (14%) of2-ethyl-5-formyl-4-methylbenzoic acid as a yellow solid.

Compound 211.5.4-(1-(2-Ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4, 450 mg, 2.34mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). DIEA (907 mg, 7.02mmol, 3.00 equiv) and HBTU (1.30 g, 3.43 mmol, 1.50 equiv) were added tothe reaction mixture. The resulting solution was stirred for 30 min at25° C. A solution of 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 624 mg, 2.80 mmol, 1.20 equiv) in DIEA (2 mL) was addeddropwise. The resulting solution was stirred for 30 min at 25° C., thenquenched with 20 mL of water. The aqueous phase was extracted with 3×30mL of ethyl acetate. The combined organic layers were washed with 1×50mL of brine, dried over anhydrous sodium sulfate and concentrated invacuo. The residue was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (5:1) as eluent to furnish 720 mg(85%) of the title compound as a yellow solid.

Compound 211.6.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid

To a round-bottom flask was added a solution of4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20mL). A solution of KMnO₄ (640 mg, 4.05 mmol, 2.00 equiv) in water (20mL) was added dropwise. The resulting solution was stirred for 15 h at60° C. then cooled to rt with a water bath. The solids were removed withfiltration. The filtrate was extracted with 3×30 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. This resulted in 600 mg (80%) of544-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acidas a light yellow solid.

Compound 211.7. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate

To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid(compound 211.6, 600 mg, 1.59 mmol, 1.00 equiv) in methanol (30 mL). Tothis was added sulfuric acid (500 mg, 5.10 mmol, 3.20 equiv) dropwise.The resulting solution was stiffed for 15 h at 60° C. After cooling toambient temperature, the mixture was concentrated in vacuo. The residuewas diluted with 20 mL of H₂O. The aqueous phase was extracted with 3×20mL of ethyl acetate. The combined organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo. This resulted in 500mg (80%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate as ayellow oil.

Compound 211.8.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide

To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoate(compound 211.7, 500 mg, 1.28 mmol, 1.00 equiv) in ethanol (20 mL).Hydrazine (4 mL) was added to the reaction mixture. The resultingsolution was stirred for 15 h at 80° C., then concentrated in vacuo. Theresidue was partitioned between water and ethyl acetate. The aqueouslayer was extracted with ethyl acetate (2×). The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo toyield 400 mg (80%) of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazideas a light yellow solid.

Compound 211.9. N-(Morpholine-4-carbonothioyl)benzamide

To a 50-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was added a solution ofmorpholine (1.00 g, 11.5 mmol, 1.00 equiv) in acetone (10 mL). TEA (1.74g, 17.2 mmol, 1.50 equiv) was added to the reaction, and the resultingsolution was stirred for 30 min at 25° C. Benzoyl isothiocyanate (1.87g, 11.5 mmol, 2.00 equiv) was added dropwise to the reaction at 0° C.The resulting solution was stirred for 30 min at 0° C., then quenchedwith 20 mL of water. The mixture was extracted with 2×30 mL of ethylacetate. The combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10-1:3) as eluentto furnish 2.30 g (80%) of N-(morpholine-4-carbonothioyl)benzamide as ayellow solid.

Compound 211.10. Morpholine-4-carbothioamide

To a round-bottom flask was added a solution ofN-(morpholine-4-carbonothioyl)benzamide (compound 211.9, 3.00 g, 12.0mmol, 1.00 equiv) in methanol (20 mL). A solution of sodium hydroxide(1.44 g, 36.0 mmol, 3.00 equiv) in water (20 mL) was added to thereaction. The resulting solution was stirred overnight at 60° C. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The residue was extracted with 2×20 mL of ethylacetate/petroleum ether(1:1). The combined organic layers were driedover anhydrous sodium sulfate and concentrated in vacuo. This resultedin 430 mg (25%) of morpholine-4-carbothioamide as a yellow solid.

Compound 211.11. 4-(Methylsulfanyl)carboximidoylmorpholine

A solution of morpholine-4-carbothioamide (compound 211.10, 430 mg, 2.94mmol, 1.00 equiv) and iodomethane (1.25 g, 8.81 mmol, 3.00 equiv) intetrahydrofuran (10 mL) was stirred for 4 h at 25° C., then concentratedin vacuo. This resulted in 471 mg (100%) of4-(methylsulfanyl)carboximidoylmorpholine as a yellow solid.

Compound 211.4-(1-(2-Ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

To a 20-mL sealed tube was added solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzohydrazide(compound 211.8, 225 mg, 0.580 mmol, 1.00 equiv) in pyridine (10 mL).4-(Methylsulfanyl) carboximidoylmorpholine (compound 211.11, 200 mg,1.25 mmol, 1.00 equiv) was added to the reaction mixture. The resultingsolution was stirred for 3 days at 100° C. behind a blast shield. Aftercooling to room temperature, the mixture was then concentrated in vacuo.The residue was purified using silica gel column chromatography withchloroform/methanol (30:1) as eluent. The crude product (˜100 mg) waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm;mobile phase, water with 0.03% NH₃H₂O and CH₃CN (32% CH₃CN up to 55% in8 min, up to 100% in 2 min, down to 32% in 1 min); Detector, Waters 2489254&220 nm. The fractions containing pure compound were combined andlyophilized to yield 67.7 mg (24%) of the title compound as a whitesolid. m/z (ES+) 485 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.69 (d, 2H),7.49-7.31 (m, 4H), 4.90-4.80 (m, 1H), 3.83-3.81 (m, 4H), 3.79-3.65 (m,1H), 3.60-3.41 (m, 4H), 3.40-3.31 (m, 1H), 3.08-2.97 (m, 2H), 2.76-2.71(m, 2H), 2.51 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.80 (m, 3H), 1.33-1.30(m, 3H).

Compound 212.4-(1-(5-(5-((2-Methoxyethyl)(methyl)amino)-4H-1,2,4-triazol-3-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 473 (M+H)⁺.

Compound 213.4-(1-(2,4-Dimethyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 471 (M+H)⁺.

Compound 214.4-(1-(2,4-Dimethyl-5-(5-(pyrrolidin-1-yl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(2-ethyl-4-methyl-5-(5-morpholino-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 211). m/z (ES+) 455 (M+H)⁺.

Compound 215.3. 4-Cyclobutyl-2-ethyl-5-iodobenzoic acid

To a round-bottom flask, was added a solution of methyl4-cyclobutyl-2-ethyl-5-iodobenzoate (compound 181.4, 10.3 g, 30.0 mmol,1.00 equiv) in methanol (100 mL). A solution of sodium hydroxide (3.60g, 3.00 equiv) in water (10 mL) was added dropwise to the stirredreaction mixture. The resulting mixture was stirred for 2 h at 60° C.After cooling to ambient temperature, the volatiles were removed underreduced pressure. The pH of the remaining aqueous mixture was adjustedto ˜4 using HCl (aq., 1 M). The resulting precipitate was collected byfiltration and dried to yield 9.00 g (91%) of4-cyclobutyl-2-ethyl-5-iodobenzoic acid as a white solid.

Compound 215.4. 4-Cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid

To a solution of 4-cyclobutyl-2-ethyl-5-iodobenzoic acid (compound215.3, 3.30 g, 10.0 mmol, 1.00 equiv) in THF (40 mL) was added n-BuLi(2.5 M, 9.50 mL, 2.38 equiv) dropwise at −78° C. under nitrogenatmosphere. The resulting solution was stirred for another 20 min at thesame temperature, followed by the addition of a solution of dimethylcarbonate (2.70 g, 30.0 mmol, 3.00 equiv) in tetrahydrofuran (2 mL)dropwise. The reaction temperature was slowly raised to 25° C. andstirred for another 1 h, then slowly quenched with 50 mL of water. ThepH was adjusted to ˜4 with HCl (aq., 1 M) and the resulting mixture wasextracted with 100 mL of ethyl acetate. The combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:3) as eluent to furnish 1.80 g (69%) of thedesired product as a white solid.

Compound 215.5. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate

To a round-bottom flask were added a solution of4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4,1.15 g, 4.38 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equiv), HBTU (2.50g, 6.59 mmol, 1.50 equiv), and DIEA (1.07 g, 8.28 mmol, 3.00 equiv) inN,N-dimethylformamide (10 mL). The resulting solution was stirred for 1h at 25° C. The reaction was then quenched by the addition of 20 mL ofwater. The resulting mixture was extracted with 2×50 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified using silicagel column chromatography with ethyl acetate/petroleum ether (1:3) toyield 1.80 g (95%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoateas a yellow solid.

Compound 215.6.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide

To a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate(compound 215.5, 2.15 g, 4.99 mmol, 1.00 equiv) in methanol (20 mL), wasadded hydrazine hydrate (80%, 15 mL) batchwise. The reaction was stirredat 80° C. overnight. After cooling to ambient temperature, the mixturewas concentrated under reduced pressure. The residue was extracted withdichloromethane (2×100 mL). The combined organic layers were dried overanhydrous magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel chromatography with dichloromethane/methanol(100:1) to furnish 1.13 g (53%) of the desired product as a pinkishsolid.

Compound 215.7.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide(compound 215.6, 600 mg, 1.39 mmol, 1.00 equiv) in 1,4-dioxane (10 mL)was added 10 mL of an aqueous solution of sodium bicarbonate (350 mg,4.17 mmol, 1.00 equiv). Cyanogen bromide (220 mg, 2.08 mmol, 1.50 equiv)was added to the reaction mixture dropwise. The reaction mixture wasstirred at 25° C. for 2 h, then quenched with 20 mL of FeSO₄(aq., sat.)and diluted with DCM. The resulting mixture was stirred vigorously thenfiltered through celite and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×50 mL of DCM. The combined organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo. This resulted in 600mg (95%) of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrileas an off-white solid.

Compound 215.8.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide

To a 10-mL sealed tube, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215.7, 228 mg, 0.500 mmol, 1.00 equiv) in ethanol (5 mL). Thiswas followed by the addition of potassium hydroxide (280 mg, 4.99 mmol,10.0 equiv) in portions. The resulting solution was stirred for 5 h at80° C. behind a blast shield. After cooling to ambient temperature, thereaction was then quenched by the addition of 15 mL of water andextracted with 2×20 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated in vacuo. Thisresulted in 200 mg (80%) of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamideas a yellow solid.

Compound 215.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of compound 215.8 (251 mg,0.500 mmol, 1.00 equiv) in dichloromethane (5 mL). This was followed bythe addition of (CF₃C0)₂O (158 mg, 1.50 equiv) dropwise with stiffing.Triethylamine (101 mg, 1.00 mmol, 2.00 equiv) was added dropwise withstirring. The resulting mixture was stirred at 25° C. for 1 h, thenconcentrated in vacuo. The residue was purified using silica gel columnchromatography with dichloromethane/methanol (20:1) as eluent. The crudeproduct (120 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (54.0% CH₃CN up to 64.0% in6 min, up to 100.0% in 1 min, down to 54.0% in 1 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 60 mg (25%) of the title compound as a whitesolid. m/z (ES+) 484 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.64 (d, 2H),7.45-7.21 (m, 4H), 4.37 (q, 2H), 4.02-3.96 (m, 1H), 3.60-3.53 (m, 1H),3.29-3.19 (m, 2H), 2.98-2.90 (m, 2H), 2.76-2.61 (m, 2H), 2.15-2.12 (m,2H), 2.07-1.92 (m, 4H), 1.80-1.68 (m, 4H), 1.35 (t, 3H), 1.29-1.20 (m,3H).

Compound 216.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215). m/z (ES+) 470 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.64(d, 2H), 7.45-7.38 (m, 3H), 7.32 and 7.21 (2 singlets, amide rotamers,1H), 4.0 (s, 3H), 4.00-3.95 (m, 1H), 3.63-3.56 (m, 1H), 3.29-3.19 (m,2H), 2.98 (app t, 2H), 2.76-2.61 (m, 2H), 2.17-1.89 (m, 6H), 1.80-1.64(m, 4H), 1.32-1.20 (m, 3H).

Compound 217.1. Methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate

To a round-bottom flask was added a solution of4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4,70.0 mg, 0.270 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL). HBTU(210 mg, 0.550 mmol, 2.07 equiv), DIEA (150 mg, 1.16 mmol, 4.35 equiv)were added to the reaction mixture at 0° C., and stirred for 30 min.This was followed by the addition of4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2HClsalt, 80.0 mg, 0.330 mmol, 1.20 equiv). The resulting solution wasstiffed for 15 h at 25° C., and then quenched with 20 mL of ice-water.The mixture was extracted with 2×50 mL of ethyl acetate. The combinedorganic layers were washed with 1×50 mL of brine, dried over anhydroussodium sulfate, and concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (1:100-1:5) as eluent to yield 100 mg (84%) of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoateas a white solid.

Compound 217.2.5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide

To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate(compound 217.1, 1.10 g, 2.45 mmol, 1.00 equiv) in ethanol (40 mL).Hydrazine hydrate (20 mL) was added to the reaction mixture, and thereaction was stirred 80° C. for 15 h. After cooling to ambienttemperature, the mixture was concentrated in vacuo, then diluted with 50mL of H₂O. The resulting mixture was extracted with 3×50 mL ofdichloromethane. The combined organic layers were washed with 2×50 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated in vacuo.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:1-1:0) as eluent to yield 900 mg (82%)of5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazideas a white solid.

Compound 217.3.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzohydrazide(compound 217.2, 450 mg, 1.00 mmol, 1.00 equiv) in 1,4-dioxane (10 mL).A solution of sodium bicarbonate (252 mg, 3.00 mmol, 2.99 equiv) inwater (10 mL) and BrCN (128 mg, 1.21 mmol, 1.20 equiv) were added to thereaction mixture. The resulting solution was stirred for 3 h at roomtemperature, then quenched with 30 mL of FeSO₄ (aq., sat.) and dilutedwith ethyl acetate. The resulting mixture was stirred vigorously thenfiltered through celite and washed with 1 M FeSO₄, water, and ethylacetate. The layers were separated and the aqueous phase was extractedwith 2×50 mL of ethyl acetate. The combined organic layers were washedwith 2×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. This resulted in 400 mg (84%) of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrileas a light brown solid.

Compound 217.4-(1-(4-Cyclobutyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-(1-(5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 217.3, 200 mg, 0.420 mmol, 1.00 equiv) in methanol (20 mL).Potassium hydroxide (237 mg, 4.22 mmol, 10.0 equiv) was added to thereaction mixture. The resulting solution was stirred for 15 h at 70° C.After cooling to ambient temperature, the organic solvent was removedunder reduced pressure. The residue was diluted with 30 mL of H₂O, thenextracted with 2×50 mL of ethyl acetate. The combined organic layerswere washed with 2×50 mL of brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (49.0% CH₃CN up to 63.0% in 8 min, up to 100.0% in 1 min,down to 49.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 20 mg(10%) of the title compound as a white. m/z (ES+) 488 (M+H)⁺. ¹H-NMR(300 MHz, CD₃OD): δ 7.72 (d, 2H), 7.64-7.61 (m, 2H), 7.39-7.25 (m, 2H),4.85-4.78 (m, 1H), 4.00-3.93 (m, 4H), 3.54-3.49 (m, 2H), 3.28-3.22 (m,1H), 2.80-2.65 (m, 2H), 2.26-1.84 (m, 10H), 1.45-1.27 (m, 3H).

Compound 218.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile(compound 215) and using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 502 [M+H]⁺, 543 [M+CH₃CN+H]⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.73(d, 2H), 7.64-7.58 (m, 2H), 7.39-7.26 (m, 2H), 4.89-4.82 (m, 1H), 4.35(q, 2H), 4.10-3.95 (m, 1H), 3.50-3.38 (m, 2H), 3.30-3.27 (m, 1H),2.75-2.65 (m, 2H), 2.22-1.86 (m, 10H), 1.41 (t, 3H), 1.35-1.20 (m, 3H).

Compound 219.1 Methyl 2-bromo-4-methylbenzoate

To a solution of 2-bromo-4-methylbenzoic acid (10 g) in MeOH (50 ml) wasadded dropwise concentrated sulfuric acid (10 ml) at 0° C. The mixturewas heated at 70° C. for 2 hours. After cooling to ambient temperature,the methanol was removed under reduced pressure. The residue was pouredinto ice-water (100 ml). The mixture was extracted with EtOAc (×2). Thecombined organic layers were washed with NaHCO₃ (aq. sat. Note: gasevolution), brine, dried over MgSO₄, filtered, and concentrated to givethe product as a clear oil. Yield: 10.5 g, 99%. ¹H NMR (400 MHz,Chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H), 7.19-7.11 (m, 1H), 3.92 (s,3H), 2.36 (s, 3H).

Compound 219.2 Methyl 2-cyclobutyl-4-methylbenzoate

-   -   Cyclobutylzinc(II) bromide (50 ml, 0.5M in THF, 25.0 mmol) was        added to a mixture of methyl 2-bromo-4-methylbenzoate (219.1,        5.0 g, 21.8 mmol) and PdCl₂(dppf)CH₂Cl₂ (1.78 g, 2.20 mmol). The        mixture was degassed and the flask was filled with argon through        a balloon. After the mixture was heated at 65° C. under argon        for 24 hours, it was cooled to 0° C. and quenched with water (10        ml). The mixture was diluted with EtOAc (200 ml), washed with        water then with brine. The EtOAc layer was dried (Na₂SO₄),        concentrated, and purified using column (silica gel)        chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 3.6 g, 81%.        ¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, 1H), 7.23-7.17 (s,        1H), 7.03 (d, 1H), 4.16 (m, 1H), 3.86 (s, 3H), 2.39 (s, 3H),        2.34 (m, 2H), 2.16-1.96 (m, 3H), 1.80 (m, 1H).

Compound 219.3 Methyl 2-cyclobutyl-5-iodo-4-methylbenzoate

N-Iodosuccinimide (5.25 g, 23.3 mmol) was added portionwise to asolution of methyl 2-cyclobutyl-4-methylbenzoate (219.2, 4.77 g, 23.3mmol) in concentrated sulfuric acid (100 ml) at 0° C. The mixture turnedvery thick after it was stirred at 0° C. for 30 min and at RT for 2hours. The mixture was cooled to 0° C. again and MeOH (100 ml) wasadded. The mixture was heated at 60° C. for 2 hours. The methanol wasremoved under reduced pressure and the residue was poured into ice water(200 ml). The mixture was extracted with EtOAc (2×). The combinedorganic layers were washed with brine, then aq. 1N NaHCO₃, dried(Na₂SO₄), and concentrated. The residue was purified using column(silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 5.0 g,clear oil, 65%. ¹H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s,1H), 4.17-4.04 (m, 1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m,2H), 2.13-1.92 (m, 3H), 1.85-1.75 (m, 1H).

Compound 219.4 Methyl 5-cyano-2-cyclobutyl-4-methylbenzoate

A mixture of methyl 2-cyclobutyl-5-iodo-4-methylbenzoate (219.3, 3.0 g,9.1 mmol), Zn(CN)₂ (2.3 g, 19.6 mmol) and Pd(PPh₃)₄ (0.55 g, 0.47 mmol)in DMF (50 ml) was degassed and the flask was filled with argon througha balloon. The mixture was heated at 100° C. under argon overnight.After cooling to ambient temperature, the reaction was quenched withsaturated aq. FeSO₄ (20 ml) and diluted with EtOAc (200 ml). The mixturewas stirred vigorously then filtered through celite and washed with 1 MFeSO₄, water and ethyl acetate. The layers were separated and theaqueous phase was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄), and concentrated. Theresidue was purified using column (silica gel) chromatography(hexanes:EtOAc 30:1 to 20:1). Yield: 2.0 g, 96%. ¹H NMR (400 MHz,Chloroform-d) δ 8.03 (s, 1H), 7.34 (s, 1H), 4.26-4.13 (m, 1H), 3.89 (s,3H), 2.59 (s, 3H), 2.46-2.32 (m, 2H), 2.16-1.98 (m, 3H), 1.90-1.78 (m,1H).

Compound 219.5. 5-Cyano-2-cyclobutyl-4-methylbenzohydrazide

To a solution of methyl 5-cyano-2-cyclobutyl-4-methylbenzoate (219.4,2.0 g, 8.73 mmol) in EtOH (10 ml) was added anhydrous hydrazine (2 ml,excess) at room temperature. The mixture was heated at 90° C. overnight.After cooling to ambient temperature, the mixture was partitionedbetween water (60 ml) and EtOAc (200 ml). The EtOAc layer was washedwith water (×2), brine, dried with Na₂SO₄, and concentrated to give theproduct as a white solid. Yield: 1.9 g, 95%. m/z (ES+) 230 (M+H)⁺. ¹HNMR (400 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.32 (s, 1H), 6.91 (br, 1H),4.08 (br, 2H), 3.89 (m, 1H), 2.61-2.52 (m, 3H), 2.42-2.28 (m, 2H),2.18-1.98 (m, 3H), 1.91-1.78 (m, 1H).

Compound 219.6.5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile

The title compound (0.55 g, white solid, 100%) was prepared using aprocedure similar to that used for the preparation of compound 217.3 andusing compound 219.5 (0.50 g) in place of compound 217.2. m/z (ES+) 255(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.45 (s, 1H),5.10 (br, 2H), 4.38 (m, 1H), 2.61 (s, 3H), 2.48-2.34 (m, 2H), 2.17-1.98(m, 3H), 1.91-1.79 (m, 1H).

Compound 219.7.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile

To a solution of5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile(219.6, 0.5 g, 2.0 mmol) in EtOH (40 ml) was added KOH (1.11 g, 20.0mmol). The mixture was heated at 85° C. overnight. After cooling toambient temperature, the mixture was neutralized to pH 7 with 1N HCl at0° C. and then extracted with EtOAc (×2). The combined organic layerswere dried (Na₂SO₄) and concentrated. The residue was purified usingcolumn (silica gel) chromatography (hexanes:EtOAc 1:1 to EtOAc). Yield:0.2 g, white solid, 34%. m/z (ES+) 283 (M+H)⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.84 (s, 1H), 7.35 (s, 1H), 4.48 (t, 2H), 4.19-4.10 (m,1H), 2.58 (s, 3H), 2.30-2.19 (m, 2H), 2.11-1.95 (m, 3H), 1.85-1.76 (m,1H), 1.45 (t, 3H).

Compound 219.8.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide

To a solution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile(219.7, 0.15 g, 0.53 mmol) in EtOH (10 ml) was added NH₄OH (0.18 ml,2.66 mmol, 14.8 N in H₂O) followed by H₂O₂ (1.8 ml, 26.6 mmol, 50% inH₂O). The mixture was stirred at room temperature overnight. The mixturewas cooled to 0° C. and quenched carefully with 1N Na₂S₂O₃ solution (26ml). The mixture was extracted with EtOAc (×2) and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified with prep-TLC (5% MeOH in CH₂Cl₂). Yield: 0.1 g, whitesolid, 62.5%. m/z (ES−) 299 (M−H)⁻.

Compound 219.9.4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid

To a solution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide(219.8, 0.1 g, 0.33 mmol) in TFA (5 ml) was added NaNO₂ (0.046 g, 0.66mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour then at roomtemperature for 2 hours. The mixture was concentrated under reducedpressure. The residue was partitioned between EtOAc and brine. Theaqueous layer was extracted with EtOAc. The combined organic layers weredried (Na₂SO₄) and concentrated to give a clear oil. Yield: 0.1 g, 100%.m/z (ES−) 300 (M−H)⁻.

Compound 219.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

A solution of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 219.9, 40 mg, 0.13 mmol), DIEA (0.07 ml, 0.39 mmol), HOBT (34mg, 0.19 mmol, with 20% water), EDCI (38 mg, 0.19 mmol), and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 36 mg, 0.16mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at roomtemperature. The reaction mixture was then diluted with 50 mL of ethylacetate and washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was applied onto a silica gel prep-TLC plate and developed usingethyl acetate/hexanes (1:1) to yield 0.1 g (68%) of the title compoundas a white solid. m/z (ES+) 470 (M+H)⁺.

Compound 220.4-(1-(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 219), using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 488 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ 11.10 (br s, 1H),7.72-7.63 (m, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.42 & 7.33 (2 singlets,amide rotamers, Ar—H, 1H), 7.25 (s, 1H), 4.86 (br d, J=11.2 Hz, 1H),4.41 (q, J=7.1 Hz, 2H), 4.17-4.03 (m, 1H), 3.61-3.38 (m, 2H), 3.29-3.14(m, 1H), 2.46-1.70 (m, 13H), 1.45 (t, J=7.2 Hz, 3H).

Compound 221.(4-Cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 219). m/z (ES+) 531(M+H)⁺.

Compound 222.1.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile(compound 219.7), except MeOH was used as the solvent instead of EtOH.m/z (ES+) 269(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 10.96 (br, 1H),7.82 (s, 1H), 7.35 (s, 1H), 4.11 (s, 3H), 4.15-4.05 (m, 1H), 2.59 (s,3H), 2.31-2.16 (m, 2H), 2.14-1.89 (m, 3H), 1.87-1.71 (m, 1H).

Compound 222.2.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzamide(compound 219.8) but using compound 222.1 in place of compound 219.7.m/z (ES+) 287(M+H)⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.50 (s, 1H), 7.33(s, 1H), 4.03 (s, 3H), 3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m,2H), 2.11-1.88 (m, 3H), 1.83-1.71 (m, 1H).

Compound 222.3.4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-cyclobutyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 219.9) but using compound 222.2 in place of compound 219.8.m/z (ES+) 287 (M+H)⁺.

Compound 222.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

A solution of4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid(compound 222.3, 60 mg, 0.2 μmol), DIEA (0.11 ml, 0.63 mmol), HOBT (53mg, 0.32 mmol, with 20% water), EDCI (60 mg, 0.32 mmol) and4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 47 mg, 0.21mmol) in N,N-dimethylformamide (3 mL) was stirred overnight at roomtemperature. The reaction mixture was then diluted with 50 mL of ethylacetate and washed with 2×20 mL of brine. The mixture was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was applied onto a silica gel prep-TLC plate and developed usingethyl acetate/hexanes (1:1) to yield 21.0 mg (22%) of the title compoundas a white solid. m/z (ES+) 456 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d)611.54-10.86 (br s, 1H), 7.60 (d, 2H), 7.38-7.20 (m, 4H), 5.04-4.92 (m,1H), 4.06 (s, 3H), 4.14-4.00 (m, 1H), 3.62 (d, 1H), 3.15-3.03 (m, 1H),2.93-2.76 (m, 2H), 2.38 and 2.30 (2 singlets, amide rotamers, ArCH₃,3H), 2.34-2.22 (m, 1H), 2.20-2.06 (m, 2H), 2.05-1.84 (m, 3H), 1.61-1.45(m, 1H).

Compound 223.4-(1-(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 222) but using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 474(M+H)⁺.

Compound 224.(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(222). m/z (ES+) 499 (M+H)⁺.

Compound 225.(4-Cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylphenyl)(4-fluoro-4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)methanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(Compound 222). m/z (ES+) 517 (M+H)⁺.

Compound 226.3. Methyl 4-cyclopropyl-2-ethylbenzoate

To a stirred mixture of ZnBr₂ (37.0 g, 164 mmol, 3.99 equiv) intetrahydrofuran (150 mL) under nitrogen was addedbromo(cyclopropyl)magnesium (3.28 M in THF, 50 mL, 4.00 equiv) dropwiseat 0° C. After stirring at 15 minutes at 0° C., the temperature waslowered to −30° C. followed by the dropwise addition of a solution ofPd(dppf)Cl₂ (2.00 g, 2.73 mmol, 0.07 equiv) in tetrahydrofuran (50 mL)and a solution of methyl 4-bromo-2-ethylbenzoate (compound 181.2, 10.0g, 41.1 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). The resultingsolution was warmed slowly to 25° C. and stiffed for 15 h, thencarefully quenched by slow addition of 100 mL of NH₄Cl (aq.sat.). Themixture was extracted with 2×100 mL of ethyl acetate and the combinedorganic layers were dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30) as eluent toyield 7.50 g (89%) of methyl 4-cyclopropyl-2-ethylbenzoate as a lightyellow oil.

Compound 226.4. Methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate

To a round-bottom flask was added a solution of methyl4-cyclopropyl-2-ethylbenzoate (compound 226.3, 5.00 g, 24.5 mmol, 1.00equiv) in AcOH (40 mL). I₂ (6.80 g, 26.8 mmol, 1.10 equiv), NaIO₄ (2.60g, 12.2 mmol, 0.50 equiv), and sulfuric acid (400 mg, 4.08 mmol, 0.15equiv) were added to the reaction. The resulting solution was stirredfor 2 h at 50° C. After cooling to ambient temperature, the reaction wascarefully quenched with Na₂S₂O₃ (aq., sat.). The mixture was extractedwith 2×100 mL of ethyl acetate, and the combined organic layers weredried over sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with petroleumether/ethyl acetate (20:1) as eluent to furnish 4.00 g (49%) of methyl4-cyclopropyl-2-ethyl-5-iodobenzoate as a yellow oil.

Compound 226.5. 4-Cyclopropyl-2-ethyl-5-iodobenzoic acid

To a solution of methyl 4-cyclopropyl-2-ethyl-5-iodobenzoate (compound226.4, 2.50 g, 7.57 mmol, 1.00 equiv) in methanol (40 mL) was addedaqueous sodium hydroxide (3.10 g, 77.5 mmol, 10.0 equiv, in 10 mLwater). The resulting mixture was stirred for 15 h at 60° C. in an oilbath. After cooling to ambient temperature, the organic solvent wasremoved under reduced pressure and pH of the remaining aqueous layer wasadjusted to 4 with hydrogen chloride (aq, 1 M). The solids werecollected by filtration and dried in an oven under reduced pressure toyield 2.20 g (92%) of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid as awhite solid.

Compound 226.6. 4-Cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid

To a solution of 4-cyclopropyl-2-ethyl-5-iodobenzoic acid (compound226.5, 500 mg, 1.58 mmol, 1.00 equiv) in THF/Et₂O (10/10 mL) undernitrogen at −78° C. was added dropwise n-butyllithium (2.5 M, 1.88 mL,3.00 equiv) over 3 min. After stirring for 10 min at −78° C., methylchloroformate (230 mg, 2.43 mmol, 1.50 equiv) was added dropwise at −78°C. The resulting solution was stirred for 40 min at −78° C., then warmedslowly to −35° C. The reaction was carefully quenched with 2 mL ofwater. The pH was adjusted to ˜4-5 with hydrogen chloride (aq., 1 M).The resulting mixture was extracted with 3×20 mL of ethyl acetate andthe combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to yield 400 mg the title compound as a yellow solid.

Compound 226.7. Methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate

To a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid(compound 226.6, 150 mg, 0.600 mmol, 1.00 equiv) inN,N-dimethylformamide (15 mL) were added4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2, 150mg, 0.620 mmol, 1.00 equiv), DIPEA (450 mg, 3.49 mmol, 6.00 equiv), andHBTU (300 mg, 0.790 mmol, 1.30 equiv). The resulting solution wasstirred for 4 h at 20° C., then quenched by the addition of 20 mL ofbrine. The resulting mixture was extracted with 4×30 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified via silicagel column with ethyl acetate/petroleum ether (1:3) as eluent. Thisresulted in 0.200 g (76%) of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoateas a light yellow solid.

Compound 226.8.5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide

To a solution of methyl5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate(compound 226.7, 200 mg, 0.460 mmol, 1.00 equiv) in ethanol (15 mL) wasadded hydrazine hydrate (80%, 5 mL). The resulting solution was stirredat 80° C. for 15 h. After cooling to ambient temperature, the reactionwas quenched with 50 mL of water, then extracted with 3×50 mL ofdichloromethane. The combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo to yield 150 mg (75%) of5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazideas a colorless oil.

Compound 226.9.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound (50 mg, white solid, 95%) was prepared using aprocedure similar to that used for the preparation of compound 217.3 andusing compound 226.8 (50 mg) in place of compound 217.2.

Compound 226.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound (50 mg, white solid, 95%) was prepared using aprocedure similar to that used for the preparation of compound 219.7 andusing compound 226.9 (300 mg) in place of compound 219.6. The crudeproduct (−30 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (46.0% CH₃CN up to 57.0% in8 min, up to 100.0% in 1 min, down to 46.0% in 1 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure compound were combinedand lyophilized to yield 15 mg of the title compound as a white solid.m/z (ES+) 474 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.73 (d, 2H),7.65-7.57 (m, 2H), 7.46-7.32 (m, 1H), 7.03 (s, 1H), 4.85-4.73 (m, 1H),4.00 (s, 3H), 3.48-3.32 (m, 2H), 3.28-3.21 (m, 1H), 2.71-2.62 (m, 2H),2.28-2.14 (m, 2H), 2.10-1.80 (m, 3H), 1.28-1.20 (m, 3H), 0.97-0.94 (m,2H), 0.75-0.50 (m, 2H).

Compound 227.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of4-(1-(4-cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 226). m/z (ES+) 488 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD):δ7.80-7.78 (m, 2H), 7.70-7.63 (m, 2H), 7.51 (m, 1H), 7.07 (s, 1H),4.89-4.82 (m, 1H), 4.40 (app t, 2H), 3.57-3.52 (m, 2H), 3.28-3.25 (m,1H), 2.80-2.50 (m, 2H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 1H), 1.45 (t,3H), 1.32-1.22 (m, 3H), 1.01-0.99 (m, 2H), 0.73-0.73 (m, 2H).

Compound 228.1. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate

To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6.,500 mg, 2.01 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL). HBTU(1.53 g, 4.03 mmol, 2.00 equiv), DIEA (780 mg, 6.04 mmol, 3.00 equiv)were added to the reaction solution, and it was stirred for 5 min at 25°C. 4-(piperidin-4-yl)benzonitrile (compound 1.5, 410 mg, 2.20 mmol, 1.10equiv) was added to the above mixture. After stirring for 15 h at 25°C., the reaction was quenched by the addition of water. The mixture wasextracted with 100 mL of ethyl acetate and the combined organic layerswere washed with 4×40 mL of brine, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (4:1) as eluentto furnish 0.830 g (99%) of methyl54444-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoateas a colorless oil.

Compound 228.2.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazide

To a round-bottom flask was added a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate(compound 228.1, 830 mg, 1.99 mmol, 1.00 equiv) in ethanol (15 mL).Hydrazine (5 mL, 100 equiv) was added to the reaction. The resultingsolution was stirred for 15 h at 100° C., then concentrated in vacuo.The residue was extracted with 100 mL of dichloromethane and thecombined organic layers were washed with 1×30 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo. This resulted in0.800 g (96%) of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzohydrazideas a white solid.

Compound 228.3.4-(1-(5-(5-Amino-1,3,4-oxadiazol-2-yl)-4-cyclopropyl-2-ethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound (750 mg, light brown solid, 94%) was prepared using aprocedure similar to that used for the preparation of compound 217.3 andusing compound 228.2 (750 mg) in place of compound 217.2.

Compound 228.4.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide

The title compound (80 mg, yellow solid, 36%) was prepared using aprocedure similar to that used for the preparation of compound 219.7 andusing compound 228.3 (200 mg) in place of compound 219.6.

Compound 228.4-(1-(4-Cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of4-(1-(4-cyclopropyl-5-(5-ethoxy-4H-1,2,4-triazol-3-yl)-2-ethylbenzoyl)piperidin-4-yl)benzamide(compound 228.4, 80.0 mg, 0.160 mmol, 1.00 equiv) in dichloromethane (10mL). Trifluoroacetic anhydride (34.0 mg, 0.160 mmol, 1.00 equiv) andtriethylamine (33.0 mg, 0.330 mmol, 2.00 equiv) were added dropwise tothe stirred mixture. The resulting solution was stirred for 2 h at 25°C., then washed with 1×10 mL of brine. The aqueous layer was extractedwith 2×20 mL of dichloromethane and the combined organic layers weredried over anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct (30 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (42% CH₃CN up to 57% in 8min, up to 100% in 1.5 min, down to 42% in 1 min); Detector, Waters 2489254&220 nm. The fractions containing pure compound were combined andlyophilized to yield 15 mg (20%) of the title compound as a an off-whitesolid. m/z (ES+) 470 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.64 (d,2H), 7.46-7.28 (m, 3H), 7.02-7.01 (m, 1H), 4.89-4.80 (m, 1H), 4.40-4.33(m, 2H), 3.58-3.56 (m, 1H), 3.27-3.25 (m, 1H), 3.04-2.90 (m, 2H),2.73-2.58 (m, 2H), 2.31-2.29 (m, 1H), 1.94-1.96 (m, 1H), 1.82-1.78 (m,3H), 1.45 (t, 3H), 1.32-1.12 (m, 3H), 0.98-0.88 (m, 2H), 0.71-0.68 (m,2H).

Compound 229.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound228. m/z (ES+) 456 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.64 (d, 2H),7.43-7.27 (m, 3H), 7.03-7.02 (m, 1H), 4.0 (s, 3H), 3.59-3.55 (m, 1H),3.28-3.27 (m, 1H), 3.04-2.98 (m, 2H), 2.97-2.56 (m, 2H), 2.53-2.29 (m,1H), 2.0-1.98 (m, 1H), 1.76-1.42 (m, 3H), 1.30-1.16 (m, 3H), 0.99-0.94(m, 2H), 0.70-0.64 (m, 2H).

Compound 230.1. 4-Cyclobutyl-5-iodo-2-methylbenzoic acid

To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound152.3, 35.0 g, 106 mmol, 1.00 equiv) in methanol (200 mL) at 0-5° C. wasadded dropwise aqueous sodium hydroxide (12.7 g, 318 mmol, 3.00 equiv in100 mL water). The resulting mixture was stirred for 3 h at 60° C. Aftercooling to ambient temperature, the organic solvent was then removedunder reduced pressure. The pH of the remaining aqueous phase wasadjusted to ˜4 with hydrogen chloride (aqueous, 2 M). The resultingsolids were collected by filtration and dried in an oven under reducedpressure to yield 31.0 g (93%) of the title compound as a white solid.

Compound 230.2. 4-Cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid.

To a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound230.1, 3.00 g, 9.49 mmol, 1.00 equiv) in THF (40 mL) under nitrogen at−78° C. was added dropwise n-BuLi (9.5 mL, 2.50 equiv, 2.5 M in THF).After 10 minutes, a solution of dimethyl carbonate (2.56 g, 28.4 mmol,3.00 equiv) in THF (10 mL) was added dropwise at −78° C. The resultingsolution was stirred for 1 h at −78° C., then carefully quenched by slowaddition of 50 mL of water. The pH was adjusted to ˜4 with hydrogenchloride (aq., 1 M). The resulting mixture was extracted with 2×80 mL ofethyl acetate, the combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:10-1:2) as eluent to furnish 1.30 g (55%) of4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid.

Compound 230.3. Methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate

To a round-bottom flask was added a solution of4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid (compound 230.2,2.10 g, 8.46 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.88 g, 8.44mmol, 1.00 equiv), EDC.HCl (3.22 g, 16.8 mmol, 2.00 equiv), and4-dimethylaminopyridine (3.10 g, 25.4 mmol, 3.00 equiv) were added tothe reaction. The resulting solution was stirred overnight at 25° C.,then diluted with 100 mL of ethyl acetate. The mixture was washed with2×30 mL of NH₄Cl(aq., sat.) and 2×30 mL of brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(0:1-1:3) as eluent to yield 3.20 g (91%) of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoateas a white solid.

Compound 230.4.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide

The title compound (660 mg, white solid, 66%) was prepared using aprocedure similar to that used for the preparation of compound 219.5 andusing compound 230.3 (1.00 g) in place of compound 219.4.

Compound 230.4-(1-(4-Cyclobutyl-5-(5-ethyl-1,3,4-oxadiazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide(compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane (5 mL).MeSO₃H (7 mg, 0.07 mmol, 0.20 equiv), and 1,1,1-triethoxypropane (190mg, 1.08 mmol, 3.00 equiv) were added to the reaction. The resultingsolution was stirred for 20 min at 110° C., then cooled to roomtemperature and diluted with 50 mL of ethyl acetate. The organic layerwas washed with 2×20 mL of water, dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (200 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (64.0% CH₃CN up to 76.0% in 6 min, up to 100.0% in 4 min,down to 64.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 129 mg(79%) of the title compound as a white solid. m/z (ES+) 455 (M+H)⁺.¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m, 3H),5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m, 1H),3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets, amide rotamers, CH₃, 3H),2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t,3H).

Compound 231.1. Methyl 4-ethenyl-2-methylbenzoate

To a round-bottom flask, which was purged and maintained with a nitrogenatmosphere, was added a solution of methyl 4-bromo-2-methylbenzoate(compound 152.1, 14.0 g, 61.1 mmol, 1.00 equiv) in N,N-dimethylformamide(150 mL). Tributyl(ethenyl)stannane (29.3 g, 92.4 mmol, 2.00 equiv) andPd(PPh₃)₄ (7.10 g, 6.14 mmol, 0.10 equiv) were added to the reaction.The resulting mixture was stirred overnight at 100° C. in an oil bath.After cooling to room temperature, the mixture was diluted with 400 mLof ethyl acetate. The organic layer was washed with 2×400 mL of NH₄Cl(aq.) and 2×400 mL of brine, dried over anhydrous sodium sulfate, thenconcentrated in vacuo. The crude product was purified by CombiFlash withthe following conditions (IntelFlash-1): mobile phase, petroleumether/ethyl acetate=1:0 increasing to petroleum ether/ethylacetate=100:1 within 20 min; Detector, UV 254 nm. This resulted in 6.81g (63%) of methyl 4-ethenyl-2-methylbenzoate as a colorless oil.

Compound 231.2. Methyl 2-methyl-4-(3-oxocyclobutyl)benzoate

To a solution of N,N-dimethylacetamide (5.5 mL) in DCE (20 mL) undernitrogen at −15° C. was added a solution of trifluoromethanesulfonicanhydride (10 mL) in DCE (50 mL) dropwise. The mixture was then stiffedfor 10 min at −15° C. to make solution A. To another flask was addedmethyl 4-ethenyl-2-methylbenzoate (compound 231.1, 5.30 g, 0.03 mol,1.00 equiv). A solution of 2,4,6-trimethylpyridine (5.5 mL) in DCE (80mL) was added dropwise at −15° C. The resulting mixture was added intosolution A dropwise under an inert atmosphere of nitrogen. The resultingsolution was stiffed overnight at 80° C. After cooling to ambienttemperature, the mixture was carefully quenched with water. Theresulting mixture was extracted with 2×200 mL of ethyl acetate, and thecombined organic layers were washed with 3×400 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified using silica gel column chromatography with ethylacetate/petroleum ether (1:50-1:5) as eluent to furnish 2.95 g (45%) ofmethyl 2-methyl-4-(3-oxocyclobutyl)benzoate as a brown oil.

Compound 231.3. Methyl 4-(3,3-difluorocyclobutyl)-2-methylbenzoate

To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of methyl2-methyl-4-(3-oxocyclobutyl)benzoate (compound 231.2, 3.00 g, 13.8 mmol,1.00 equiv) in dichloromethane (100 mL). DAST (22.2 g, 137 mmol, 10.00equiv) was added to the reaction mixture. The resulting solution wasstiffed overnight at 25° C., then carefully quenched by slowly adding(dropwise at first) 500 mL of sodium bicarbonate (aq.) and ice. Themixture was extracted with 300 mL of ethyl acetate and the combinedorganic layers were washed with 2×300 mL of sodium bicarbonate (aq.) and2×300 mL of brine, dried over anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:20) as eluent tofurnish 3.00 g (91%) of methyl4-(3,3-difluorocyclobutyl)-2-methylbenzoate as a brown oil.

Compound 231.4. Methyl4-(3,3-difluorocyclobutyl)-5-iodo-2-methylbenzoate

The title compound (3.02 g, yellow solid, 66%) was prepared using aprocedure similar to that used for the preparation of compound 181.4 andusing compound 231.3 (3.00 g) in place of compound 181.3.

Compound 231.5.4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid

The title compound was synthesized using standard chemical manipulationsand procedures similar to those used for the preparation of compound164.1 using compound 231.4 in place of compound 152.3.

Compound 231.4-(1-(4-(3,3-Difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-(3,3-difluorocyclobutyl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoicacid (compound 231.5, 211 mg, 0.660 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 146 mg, 0.660 mmol, 1.00 equiv), EDC.HCl(252 mg, 1.31 mmol, 2.00 equiv) and 4-dimethylaminopyridine (160 mg,1.31 mmol, 2.00 equiv) were added to the reaction. The resultingsolution was stirred for 3 h at 30° C. in an oil bath, then diluted with30 mL of ethyl acetate. The mixture was washed with 3×40 mL of brine,dried over anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct (448 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (48.0% CH₃CN up to 62.0% in6 min, up to 100.0% in 4 min, down to 48.0% in 2 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 186 mg (58%) of the title compound as a whitesolid. m/z (ES+) 490 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD, ppm): δ 7.68 (d,J=8 Hz, 2H), 7.59-7.44 (m, 4H), 4.89-4.80 (m, 1H), 4.03-3.98 (m, 1H),3.67-3.61 (m, 1H), 3.28-3.24 (m, 1H), 3.04-3.00 (m, 2H), 2.97-2.89 (m,2H), 2.87-2.83 (m, 2H), 2.62-2.60 (m, 2H), 2.48 and 2.38 (2 singlets,amide rotamers, ArCH₃, 3H), 2.05-2.00 (m, 1H), 1.88-1.58 (m, 3H), 1.41(t, 3H).

Compound 232.1. Methyl5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate

A mixture of 3-bromo-N,N-dimethyl-2-oxopropanamide (246 mg), methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 237mg), and potassium carbonate (311 mg) in acetonitrile (12 ml) was heatedto reflux for 48 hours. After cooling to ambient temperature the mixturewas concentrated. The residue was dissolved in EtOAc and washed withbrine, dried over MgSO₄, concentrated, and purified by flashchromatography (SiO₂; EtOAc) to give 88 mg of the title compound. m/z(ES+) 302 (M+H)⁺.

Compound 232.2.5-(5-(Dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid

Methyl 5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoate(compound 232.1, 113 mg, 0.37 mmol) was dissolved in 2N LiOH aqueous (1ml) and tetrahydrofuran (THF) (5 ml) and heated to 50° C. for 16 hours.After cooling to ambient temperature, the organic solvent was removed invacuo. The pH of the remaining aqueous layer was adjusted with 2N HCl topH 3-4. The resulting precipitate was collected by filtration and driedto afford 56 mg of5-(5-(dimethylcarbamoyl)-1H-imidazol-2-yl)-2,4-dimethylbenzoic acid(53%). m/z (ES+) 288 (M+H)⁺.

Compound 232.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazole-5-carboxamide

A mixture of above acid (compound 232.2, 56 mg, 0.2 mmol),4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 45 mg, 0.2mmol), HBTU (152 mg, 0.4 mmol), and DIEA (105 ul, 0.6 mmol) in DMF (2ml) was stirred at room temperature for 16 hours. The reaction wasdiluted with brine and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄ and concentrated. The residue waspurified by flash chromatography (SiO₂; 4% Methanol in EtOAc) to yield44 mg of a foam (48%). m/z (ES+) 456 (M+H)⁺.

Compound 233.4-(1-(2,4-Dimethyl-5-(5-(morpholine-4-carbonyl)-1H-imidazol-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of245-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-N,N-dimethyl-1H-imidazole-5-carboxamide(compound 232). m/z (ES+) 498 (M+H)⁺.

Compound 234.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid

To a solution of methyl5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate(compound 230.3, 1.50 g, 3.60 mmol, 1.00 equiv) in methanol (10 mL) wasadded aqueous sodium hydroxide (577 mg, 14.4 mmol, in 5 mL water)dropwise at 0° C. The resulting solution was stirred for 2 h at 60° C.in an oil bath. After cooling to ambient temperature, the organicsolvent was removed under reduced pressure. The pH of the remainingaqueous layer was adjusted to 3-4 with hydrogen chloride (aq., 2 M). Theresulting solids were collected by filtration and dried in an oven underreduced pressure to yield 1.20 g (83%) of the title compound as a whitesolid. m/z (ES+) 403 (M+H)⁺.

Compound 235.1.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoylchloride

To a round-bottom flask was added a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid (compound 234, 500 mg, 1.24 mmol, 1.00 equiv) in dichloromethane (5mL). Oxalyl chloride (317 mg, 2.50 mmol, 2.00 equiv) andN,N-dimethylformamide (˜5 mg) were added dropwise to the mixture. Theresulting solution was stirred for 1 h at 40° C., then concentrated anddried under reduced pressure to yield 480 mg (92%) of the title compoundas a light yellow oil.

Compound 235.2.4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of TMSCHN₂ (2 M in hexane) (0.476 mL, 2.00 equiv) indichloromethane (10 mL) under nitrogen at 0° C. was added dropwise asolution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoylchloride (compound 235.1, 200 mg, 0.480 mmol, 1.00 equiv) indichloromethane (3 mL). The resulting mixture was stirred overnight at25° C. HBr (40%) (0.154 mL, 1.50 equiv) was then added dropwise at 0° C.and the mixture was stirred for another 2 h at 0° C., then diluted with50 mL of dichloromethane. The organic layer was washed with 2×20 mL ofwater and 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (0:1-1:50-1:5) aseluent to furnish 200 mg (88%) of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrileas a yellow oil.

Compound 235.4-(1-(4-Cyclobutyl-5-(2-ethyl-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 235.2, 100 mg, 0.210 mmol, 1.00 equiv) in CH₃CN (5 mL).Propionimidamide hydrochloride (22.8 mg, 1.00 equiv) and potassiumcarbonate (86.6 mg, 0.63 mmol, 3.00 equiv) were added to the reaction.The resulting solution was stirred for 3 h at 80° C., then cooled toroom temperature and concentrated in vacuo. The residue was dissolved in20 mL of water. The mixture was extracted with 2×20 mL of ethyl acetateand the combined organic layers were dried over anhydrous sodium sulfateand concentrated in vacuo. The crude product (˜100 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (29.0% CH₃CN up to 43.0% in 7 min, up to 100.0% in 3 min,down to 29.0% in 2 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 43 mg(44%) of the title compound as a white solid. m/z (ES+) 453 (M+H)⁺. ¹HNMR (300 MHz, CD₃OD): δ 7.68 (d with fine structure, J=7.8 Hz, 2H),7.56-7.53 (m, 4H), 7.30 and 7.20 (2 singlets, amide rotamers, Ar—H, 1H),˜4.9 (1H partially obscured by water peak), 3.84-3.70 (m, 1H), 3.70-3.53(m, 1H), 3.33-3.19 (m, 1H partially obscured by methanol solvent peak),3.13-2.92 (m, 4H), 2.48 & 2.38 (2 singlets, amide rotamers, Ar—CH₃, 3H),2.29-2.11 (m, 4H), 2.11-1.93 (m, 2H), 1.93-1.72 (m, 3H), 1.72-1.53 (m,1H), 1.45 (t, 3H).

Compound 236.1.4-(1-(5-(2-Bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 235.2) but using compound 11.2HCl salt instead of compound1.5.

Compound 236.4-(1-(4-Cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of4-(1-(5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 236.1, 40 mg, 0.08 mmol, 1.00 equiv) in CH₃CN (10 mL).Acetimidamide hydrochloride (7.6 mg, 0.08 mmol, 1.00 equiv) andpotassium carbonate (33.4 mg, 0.24 mmol, 3.00 equiv) were added to thereaction. The resulting solution was stirred for 2 h at 80° C. in an oilbath, then cooled to ambient temperature and concentrated under reducedpressure. The residue was dissolved in 50 mL of ethyl acetate. Theorganic layer was washed with 2×20 mL of water, 2×20 mL of brine, driedover anhydrous sodium sulfate and concentrated under vacuum. The crudeproduct (˜50 mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (29.0% CH₃CN up to 43.0% in8 min, up to 100.0% in 2 min, down to 29.0% in 2 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 13 mg (35%) of the title compound as a whitesolid. m/z (ES+) 457 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.78 (d, 2H),7.65 (d, 2H), 7.50-7.46 (m, 2H), 7.35 and 7.23 (2 s, amide rotamers,1H), 4.91-4.83 (m, 1H), 3.76-3.63 (m, 1H), 3.54-3.49 (m, 2H), 3.32-3.30(m, 1H), 2.70 (s, 3H), 2.49 and 2.39 (2 singlets, amide rotamers, ArCH₃,3H), 2.34-2.28 (m, 7H), 1.98-1.80 (m, 3H).

Compound 237.1. N′-Hydroxy-3-methoxypropanimidamide

Into a round-bottom flask, was placed a solution of3-methoxypropanenitrile (10.0 g, 118 mmol, 1.00 equiv) in ethanol (20mL). NH₂OH (50% in H₂O) (10 mL) was added to the reaction. The resultingsolution was stiffed overnight at 90° C. in an oil bath, then cooled toambient temperature and concentrated under reduced pressure. The residuewas diluted with 30 mL of H₂O and washed with 2×20 mL of ethyl acetate.The aqueous layers were combined and concentrated under reduced pressureto yield 10.0 g (65%) of the title compound as a colorless oil.

Compound 237.2. 3-Methoxypropanimidamide hydrochloride

Into a round-bottom flask, was placed a solution ofN′-hydroxy-3-methoxypropanamidine (compound 237.1, 10.0 g, 76.2 mmol,1.00 equiv, 90%) in AcOH (50 mL). Acetic anhydride (9.50 g, 93.1 mmol,1.10 equiv) was added dropwise and the resulting mixture was stiffed for30 min at room temperature. After purging the flask with nitrogen,palladium on carbon (10%, 60% water, 5 g) was added. The flask wascarefully purged with nitrogen again and the atmosphere was then changedto hydrogen. The mixture was stirred overnight at 20° C. underatmospheric pressure of hydrogen. After purging the system withnitrogen, the solids were then removed by filtration and the filtratewas concentrated under reduced pressure. The residue was diluted with 50mL of H₂O. The pH value of the solution was adjusted to 2-3 withhydrogen chloride (12 mol/L), then washed with 2×30 mL of ethyl acetate.The aqueous layers were combined and concentrated under reduced pressureto furnish 5.00 g (40%) of the title compound as an off-white solid.

Compound 237.4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-2-methyl-5-(2-methyl-1H-imidazol-5-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile(compound 236) and using 237.2 in place of acetimidamide hydrochloride.m/z (ES+) 501 (M+H)⁺.

Compound 238.1. Methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate

To a solution of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (152.3,5.00 g, 15.1 mmol, 1.00 equiv) in DMSO (50 mL) under nitrogen were added1-(ethenyloxy)butane (3.03 g, 30.3 mmol, 2.00 equiv), DPPP (624 mg, 1.51mmol, 0.10 equiv), Pd(OAc)₂ (324 mg, 1.51 mmol, 0.10 equiv), and TEA(3.06 g, 30.2 mmol, 2.00 equiv). The resulting mixture was stirredovernight at 120° C. under nitrogen, then cooled to ambient temperatureand diluted with water. The pH was adjusted to 1 with hydrogen chloride(aq., 6 M). The resulting mixture was diluted with 200 mL of ethylacetate, washed with brine (3×200 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30) as eluent tofurnish 2.28 g (61%) of the title compound as a yellow oil.

Compounds 238.2 and 238.3. Methyl5-(2-bromoacetyl)-4-cyclobutyl-2-methylbenzoate and methyl4-cyclobutyl-5-(2,2-dibromoacetyl)-2-methylbenzoate

To a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (238.1,500 mg, 1.83 mmol, 1.00 equiv, 90%) in chloroform (5 mL) was addeddropwise Br₂ (325 mg, 2.03 mmol, 1.00 equiv)(CAUTION: exotherm reactionwith significant evolution of HBr). The resulting mixture was stirredfor 3 h at 25° C., and then quenched by the addition of 5 mL of H₂O. Themixture was then extracted with 50 mL of ethyl acetate. The organicphase was washed with 2×10 mL of Na₂S₂O₃ (aq., sat.) followed by 1×20 mLof brine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to yield 500 mg of a mixture of the title compounds asa yellow oil.

Compound 238.4. Methyl4-cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoate

Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of a mixture of compounds238.2 and 238.3 (500 mg, ˜0.6 mmol, 80%), potassium carbonate (640 mg,3.00 equiv), 3-methoxypropanimidamide hydrochloride (compound 237.2, 213mg, 1.54 mmol) in acetonitrile. The resulting solution was stirredovernight at 80° C. in an oil bath, then cooled to ambient temperatureand concentrated under reduced pressure. The residue was diluted with 60mL of ethyl acetate. The organic layer was washed with 2×25 mL of water,2×25 mL of brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (2:1) as eluent tofurnish 90 mg (43%) of the title compound as a yellow solid.

Compound 238.5.4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoicacid

A mixture of compound 238.4, 90 mg, 0.25 mmol, 1.00 equiv, 90%) andaqueous sodium hydroxide (44 mg, 1.10 mmol, 4.00 equiv in 1 mL of water)in methanol (3 mL) was stirred for 2 h at 60° C. After cooling toambient temperature, the methanol was removed under reduced pressure.The pH of the residual aqueous layer was adjusted to 3-4 with hydrogenchloride (aqueous, 2 M). The resulting mixture was concentrated underreduced pressure to yield 80 mg (crude) of the title compound as ayellow solid.

Compound 238.4-(1-(4-Cyclobutyl-5-(2-(2-methoxyethyl)-1H-imidazol-5-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of compound 238.5 (80 mg,0.23 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (2 mL).4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 54 mg, 0.24mmol, 1.00 equiv), EDC.HCl (93 mg, 0.49 mmol, 2.00 equiv), and4-dimethylaminopyridine (59 mg, 0.48 mmol, 2.00 equiv) were added to thesolution. The resulting mixture was stirred for 3 h at 30° C., thendiluted with 50 mL of ethyl acetate. The organic layer was washed with2×20 mL of water, 2×20 mL of brine, dried over anhydrous sodium sulfate,and concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with chloroform/methanol (20:1) aseluent. The product (˜50 mg) was further purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (29%CH₃CN up to 43% in 8 min, up to 100% in 6 min, down to 29% in 1 min);Detector, Waters 2489 254&220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 20.6 mg (19%) of the titlecompound as a white solid. m/z (ES+) 483 (M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 236,237, and 238:

Cmpnd m/z # Compound Name Compound Structure (ES+) 2394-(1-(4-cyclobutyl- 5-(2-(methoxy- methyl)-1H- imidazol-5-yl)-2-methylbenzoyl)- 4-fluoropiperidin- 4-yl)benzonitrile

487 (M + H)⁺ 240 4-(1-(4-cyclobutyl- 5-(2-(methoxy- methyl)-1H-imidazol-5-yl)-2- methylbenzoyl) piperidin-4- yl)benzonitrile

469 (M + H)⁺ 241 4-(1-(4-cyclobutyl- 3-(2-methyl-1H- imidazol-5-yl)benzoyl)piperidin- 4-yl)benzonitrile

425 (M + H)⁺ 242 4-(1-(4-cyclobutyl- 2-methyl-5-(2- methyl-1H-imidazol-5-yl) benzoyl)piperidin- 4-yl)benzonitrile

439 (M + H)⁺ 243 4-(1-(4-cyclobutyl- 3-(2-(2-methoxy-ethyl)-1H-imidazol- 5-yl)benzoyl)-4- fluoropiperidin-4- yl)benzonitrile

487 (M + H)⁺ 244 4-(1-(4-cyclobutyl- 3-(2-(2-methoxyethyl)-1H-imidazol-5-yl) benzoyl)piperidin-4- yl)benzonitrile

469 (M + H)⁺

Compound 245.1. Methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoatehydrochloride

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of methyl5-(N′-hydroxycarbamimidoyl)-2,4-dimethylbenzoate (compound 2.4) andmethyl 5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5)using methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 152.4)instead of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3).

Compound 245.2. Methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate

To a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was added a solution of methyl5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound245.1, 350 mg, 1.11 mmol, 1.00 equiv, 90%) in ACN (50 mL).1-Bromobutan-2-one (186 mg, 1.23 mmol, 1.00 equiv) and potassiumcarbonate (513 mg, 3.53 mmol, 3.00 equiv, 95%) were added to thereaction. The resulting solution was stirred overnight at 80° C. Aftercooling to ambient temperature, the mixture was diluted with ethylacetate and washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:5) as eluent to furnish 290 mg (83%) of methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate as a yellowsolid.

Compound 245.3.4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid

A mixture of methyl4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoate (compound245.2, 200 mg, 0.600 mmol, 1.00 equiv, 90%) and sodium hydroxide (107mg, 2.68 mmol, 4.00 equiv) in a solvent mixture of methanol and water(4/2 mL) was stirred for 3 h at 60° C. After cooling to ambienttemperature, the pH was adjusted to 3-4 with hydrogen chloride (aq., 6M). The resulting mixture was concentrated in vacuo to yield 150 mg of awhite solid.

Compound 245.4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-cyclobutyl-5-(5-ethyl-1H-imidazol-2-yl)-2-methylbenzoic acid (compound245.3, 153 mg, 0.480 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (5mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 132 mg,0.590 mmol, 1.10 equiv), EDC.HCl (204 mg, 1.01 mmol, 2.00 equiv, 95%)and 4-dimethylaminopyridine (131 mg, 1.02 mmol, 2.00 equiv, 95%) wereadded to the reaction. The resulting solution was stirred overnight atroom temperature, then concentrated in vacuo. The residue was purifiedusing silica gel column chromatography with ethyl acetate/petroleumether (2:1) as eluent. The crude product (˜150 mg) was further purifiedby Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH₃CN (28% CH₃CN up to 43% in 7 min, up to 100% in 2 min, downto 28% in 2 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 62 mg(29%) of the title compound as a white solid. m/z (ES+) 453 (M+H)⁺. ¹HNMR (400 MHz, CD₃OD) δ 7.75-7.67 (m, 2H), 7.49-7.34 (m, 5H), 4.89-4.80(m, 1H), 3.75-3.72 (m, 1H), 3.64-3.59 (m, 1H), 3.27-3.23 (m, 1H),3.05-2.90 (m, 2H), 2.83 (q, 2H), 2.40 and 2.30 (2 singlets, amiderotamers, ArCH₃, 3H), 2.27-1.97 (m, 6H), 1.90-1.70 (m, 4H), 1.40 (t,3H).

Compound 246.1. 2-Methoxyacetyl chloride

To a solution of 2-methoxyacetic acid (2.00 g, 22.2 mmol, 1.00 equiv) indichloromethane (20 mL) was added dropwise (COCl)₂ (5.65 g, 2.00 equiv)in N,N-dimethylformamide (0.1 mL) (gas evolution observed). The reactionwas stirred for 1 h at 40° C. The resulting mixture was thenconcentrated under reduced pressure to yield 2.10 g (70%) of2-methoxyacetyl chloride as a yellow oil.

Compound 246.2. 1-Bromo-3-methoxypropan-2-one

To a solution of TMSCHN₂ (2 M in hexane) (16 mL, 2.00 equiv) indichloromethane (40 mL) was added 2-methoxyacetyl chloride (compound246.1, 2.10 g, 15.5 mmol, 1.00 equiv, 80%) dropwise at 0° C. Afterstiffing for 20 min, HBr (48%, 2 mL) was added to the reaction. Theresulting solution was stiffed for 30 min at 25° C. The mixture waswashed with 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. This resulted in 2.30 g (71%) of1-bromo-3-methoxypropan-2-one as a yellow oil.

Compound 246.3. Methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate

To a round-bottom flask was added a solution of1-bromo-3-methoxypropan-2-one (compound 246.2, 505 mg, 1.81 mmol, 1.00equiv, 60%) in CH₃CN (16 mL). Methyl5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound245.1, 450 mg, 1.59 mmol, 1.00 equiv) and potassium carbonate (554 mg,3.61 mmol, 3.00 equiv, 90%) were added to the reaction. The resultingsolution was stirred overnight at 80° C. under nitrogen. After coolingto ambient temperature, the reaction was carefully quenched by theaddition of water. The resulting mixture was extracted with 2×50 mL ofethyl acetate. The combined organic layers were dried (Na₂SO₄), andconcentrated in vacuo. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:2) as eluent tofurnish 170 mg (24%) of methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate asa white solid.

Compound 246.4.4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid

A solution of methyl4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate(compound 246.3, 150 mg, 0.430 mmol, 1.00 equiv, 90%) and aqueous sodiumhydroxide (76.0 mg, 1.90 mmol, 4.00 equiv in 2 mL water) in methanol (4mL) was stirred for 2 h at 60° C. After cooling to ambient temperature,the organic solvent was removed under reduced pressure. The pH value ofthe remaining aqueous phase was adjusted to −4 with hydrogen chloride(aq., 4 M). The resulting mixture was extracted with 2×50 mL of ethylacetate, and the combined organic layers were dried (Na₂SO₄) andconcentrated in vacuo. This resulted in 120 mg (84%) of4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acidas a white solid.

Compound 246.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid(compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) inN,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv), EDC.HCl(64.0 mg, 0.330 mmol, 2.00 equiv), and 4-dimethylaminopyridine (41.0 mg,0.340 mmol, 2.00 equiv) were added to the reaction. The resultingsolution was stirred for 3 h at 25° C., then quenched with water andextracted with 2×30 mL of ethyl acetate. The combined organic layerswere concentrated in vacuo. The crude product (˜50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05%TFA and CH3CN (26.0% CH3CN up to 42.0% in 7 min, up to 100.0% in 2 min,down to 26.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractionscontaining pure compound were combined and lyophilized to yield 18 mg(25%) of the title compound as a white solid. m/z (ES+) 469 (M+H)⁺. ¹HNMR (300 MHz, CD₃OD): δ 7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H), ˜4.9 (1Hpartially obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m, 1H),3.68-3.52 (m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partially obscured bymethanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2 singlets,amide rotamers, Ar—CH₃, 3H), 2.16-1.97 (m, 6H), 1.94-1.58 (m, 4H).

Compound 247.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246), using 4-(4-fluoropiperidin-4-yl)benzonitrilehydrochloride (compound 11.2HCl salt) instead of4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5). m/z (ES+)487 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.79-7.67 (m, 2H), 7.66 (d, 3H),7.53-7.39 (m, 2H), 4.99-4.93 (m, 1H), 4.85 (s, 2H), 3.76-3.56 (m, 3H),3.50 (s, 3H), 2.42 and 2.34 (2 singlets, amide rotamers, ArCH₃, 3H),2.27-1.97 (m, 8H), 1.92-1.81 (m, 2H), 1.35-1.26 (m, 1H).

Compound 248.4-(1-(4-Cyclobutyl-5-(5-(methoxymethyl)-4-methyl-1H-imidazol-2-yl)-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 501 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ7.79-7.77 (m, 2H), 7.66 (d, 2H), 7.52-7.38 (m, 2H), 4.87-4.80 (m, 1H),4.55 (s, 2H), 3.78-3.74 (m, 1H), 3.62-3.56 (m, 2H), 3.50 (s, 3H),3.44-3.32 (m, 1H), 2.52 and 2.42 (2 singlets, amide rotamers, ArCH₃,3H), 2.44 (s, 3H), 2.11-1.99 (m, 8H), 1.93-1.83 (m, 2H).

Compound 249.4-(1-(4-Cyclobutyl-5-(4,5-dimethyl-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of441-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 453 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.68(d, 2H), 7.51 (d, 2H), 7.31 (d, 1H), 7.32 and 7.30 (2 singlets, amiderotamers, ArH, 1H), 4.90-4.88 (m, 1H), 3.96-3.87 (m, 1H), 3.70-3.62 (m,1H), 3.32-3.29 (m, 1H), 3.02 (t, 2H), 2.44 and 2.33 (2 singlets, amiderotamers, ArCH₃, 3H), 2.20 (s, 6H), 2.18-1.90 (m, 7H), 1.88-1.78 (m,3H).

Compound 250.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of4-(1-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 439 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.68(d, 2H), 7.49-7.39 (m, 4H), 7.36 and 7.34 (2 singlets, amide rotamers,ArH, 1H), 4.90-4.86 (m, 1H), 3.75-3.70 (m, 1H), 3.63-3.55 (m, 1H),3.33-3.24 (m, 1H), 3.04-2.99 (m, 2H), 2.51 and 2.41 (2 singlets, amiderotamers, ArCH₃, 3H), 2.44 (s, 3H), 2.28-1.96 (m, 6H), 1.89-1.81 (m,3H), 1.77-1.74 (m, 1H).

Compound 251.4-(1-(4-Cyclobutyl-2-methyl-5-(5-(trifluoromethyl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of441-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 493 (M+H)⁺.

Compound 252.4-(1-(5-(5-Chloro-1H-imidazol-2-yl)-4-cyclobutyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of441-(4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 246). m/z (ES+) 459 (M+H)⁺.

Compound 253.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-1H-imidazole-5-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 246.m/z (ES+) 450 (M+H)⁺.

Compound 254.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide

To a solution of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoicacid (compound 234, 50 mg, 0.124 mmol) in DMF (2 mL) were added EDCI (36mg, 0.186 mmol), HOBt (10 mg, 0.5 mmol), diisopropylethyl amine (54 mg,0.434 mmol), and methyl amine (125 ul, 2.5 M in THF). The reactionmixture was stirred for 12 hours at room temperature and quenched withsaturated aqueous NaHCO₃ (50 mL). After extraction with ethyl acetate(2×50 mL), the combined organic layers were dried over Na₂SO₄, filtered,and concentrated in vacuo. Purification via SiO₂ flash chromatographywith ethyl acetate to ethyl acetate/methanol=98/2 afforded5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(28.3 mg, 55% yield) as a white solid. m/z (ES+) 416 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆): δ 8.13 (q, J=4.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H),7.55-7.45 (m, 2H), 7.26 (br s, 1H), 7.12 & 6.99 (2 singlets, amiderotamers, Ar—H, 1H), 4.70 (br d, J=11.9 Hz, 1H), 3.86-3.72 (m, 1H),3.50-3.35 (m, 1H), 3.13 (t with fine structure, J=12.3 Hz, 1H),2.99-2.78 (m, 2H), 2.72 (d, J=4.6 Hz, 3H), 2.39-2.17 (m, 5H), 2.17-1.98(m, 2H), 1.98-1.81 (m, 2H), 1.81-1.35 (m, 4H).

Compound 255.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-(2-methoxyethyl)-4-methylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254). m/z (ES+) 460 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27(t, 1H), 7.78 (d, 2H), 7.49 (d, 2H), 7.26 (s, 1H), 7.12 and 6.98 (2singlets, amide rotamers, 1H), 4.70 (d, 1H), 3.85-3.75 (m, 1H), 3.44 (t,3H), 3.39-3.33 (m, 2H), 3.30 (s, 3H), 3.19-3.03 (m, 1H), 3.02-2.71 (m,2H), 2.32 and 2.26 (2 singlets, amide rotamers, ArCH₃, 3H), 2.38-2.17(m, 2H), 2.15-2.00 (m, 2H), 1.98-1.81 (m, 2H), 1.83-1.47 (m, 4H).

Compound 256.5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N-ethyl-4-methylbenzamide

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254). m/z (ES+) 430 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21(t, 1H), 7.78 (d, 2H), 7.56-7.45 (m, 2H), 7.31-7.20 (m, 1H), 7.11 and6.98 (2 singlets, amide rotamers, 1H), 4.74-4.65 (m, 1H), 3.85-3.74 (m,1H), 3.50-3.37 (m, 1H), 3.22 (q, 2H), 3.20-3.05 (m, 2H), 2.32 and 2.22(2 singlets, amide rotamers, ArCH₃, 3H), 3.01-2.76 (m, 2H), 2.38-2.17(m, 2H), 2.18-1.97 (m, 2H), 1.98-1.84 (m, 2H), 1.81-1.38 (m, 3H), 1.10(t, 3H).

Compound 257.1. (S)-Tetrahydrofuran-2-carbonyl chloride

To a round-bottom flask was added a solution of(S)-tetrahydrofuran-2-carboxylic acid (4.64 g, 40.0 mmol, 1.00 equiv) indichloromethane (25 mL). N,N-dimethylformamide (0.05 mL, 0.05 equiv) and(COCl)₂ (5.2 mL, 1.50 equiv) were added dropwise to the reaction. Theresulting solution was stirred for 1 h at 25° C., then concentrated invacuo to yield 5.00 g (93%) of (9-tetrahydrofuran-2-carbonyl chloride asa yellow oil.

Compound 257.2. (S)-2-Bromo-1-(tetrahydrofuran-2-yl)ethanone

To a 250-mL three neck round-bottom flask, which was purged andmaintained with an inert atmosphere of nitrogen, was added a solution of(diazomethyl)trimethylsilane (20 mL, 2 M in hexane) in ether (150 mL). Asolution of (S)-tetrahydrofuran-2-carbonyl chloride (compound 257.1,5.00 g, 37.2 mmol, 1.00 equiv) in ether/DCM (25/10 mL) was addeddropwise at 0° C. and stirred for 20 min at 0° C. Hydrogen bromide (48%)(8 mL, 1.50 equiv) was added dropwise. The resulting solution wasstiffed for 30 min at 10° C., then washed with 2×100 mL of water and1×50 mL of brine. The mixture was dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified using silica gelcolumn chromatography with ethyl acetate/petroleum ether (1:50) aseluent to furnish 2.50 g (35%) of(S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone as a yellow oil.

Compound 257.3. (9-Methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate

To a round-bottom flask was added a solution of methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 1.30g) in CH₃CN (30 mL). (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone(compound 257.2, 1.92 g, 9.95 mmol) and potassium carbonate (4.20 g,30.4 mmol) were added to the reaction. The resulting solution wasstirred for 3 days at 75° C. under nitrogen. After cooling to ambienttemperature, the solids were removed by filtration. The filtrate wasconcentrated in vacuo and diluted with 30 mL of H₂O. The aqueous phasewas extracted with 3×50 mL of ethyl acetate and the combined organiclayers were dried over anhydrous sodium sulfate, then concentrated invacuo. The mixture was purified using silica gel column chromatographywith ethyl acetate/petroleum ether (1:2) as eluent to yield 400 mg (25%)of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as alight yellow solid.

Compound 257.4.(S)-2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoicacid

To a round-bottom flask was added a solution of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate(compound 257.3, 400 mg, 1.33 mmol, 1.00 equiv) and sodium hydroxide(300 mg, 7.50 mmol, 5.63 equiv) in a solvent mixture of methanol and H₂O(20/10 mL). The resulting solution was stirred for 2 h at 70° C. Aftercooling to ambient temperature, the organic solvent was removed underreduced pressure. The residual aqueous layer was washed with 2×50 mL ofethyl acetate. The pH of the aqueous layer was adjusted to 5-6 withhydrogen chloride (aq., 6 M), then extracted with 3×50 mL of ethylacetate. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated in vacuo. This resulted in 340 mg (90%) of(S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate as ayellow solid.

Compound 257.(S)-4-(1-(2,4-Dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of (S)-methyl2,4-dimethyl-5-(5-(tetrahydrofuran-2-yl)-1H-imidazol-2-yl)benzoate(compound 257.4, 143 mg, 0.500 mmol, 1.00 equiv) inN,N-dimethylformamide (10 mL). HBTU (285 mg, 0.750 mmol, 1.50 equiv) wasadded to the reaction, and it was stiffed for 30 min at 25° C. To thiswas added 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,133 mg, 0.600 mmol, 1.20 equiv) and DIEA (390 mg, 3.02 mmol, 6.04 equiv)dropwise. The resulting solution was stirred for 30 min at 25° C., thenquenched with 20 mL of water. The mixture was extracted with 3×25 mL ofethyl acetate and the combined organic layers were dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified usingsilica gel column chromatography with methanol/ethyl acetate (1:30) aseluent. The product (˜100 mg) was further purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge PrepC18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN(35% CH₃CN up to 52% in 8 min, up to 100% in 1 min, down to 35% in 1min); Detector, Waters 2489 254&220 nm. The fractions containing purecompound were combined and lyophilized to yield 34.6 mg (15%) of thetitle compound as a white solid. m/z (ES+) 455 (M+H)⁺.

Compound 258.1.5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid

The title compound was synthesized using standard chemical manipulationsand procedures similar to those used for the preparation of compound152.8 using 4-fluoro-2-methylbenzoic acid instead of4-bromo-2-methylbenzoic acid and propionohydrazide instead ofacetohydrazide.

Compound 258.2.4-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoic acid(compound 258.1, 125 mg, 0.500 mmol, 1.00 equiv) in DMF (10 mL). EDC.HCl(143 mg, 0.750 mmol, 1.50 equiv), 4-(piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 122 mg, 0.550 mmol, 1.10 equiv), and4-dimethylaminopyridine (183 mg, 1.50 mmol, 3.00 equiv) were added inportions. The resulting solution was stirred for 1 h at 40° C. in an oilbath, then quenched with 50 mL of NH₄Cl(aq.sat.). The mixture wasextracted with 40 mL of ethyl acetate and the combined organic layerswere washed with 3×30 mL of NH₄Cl(aq.sat.), dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 180 mg (86%) of4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrileas a white solid.

Compound 258.4-(1-(4-(Azetidin-1-yl)-5-(5-ethyl-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a 10-mL sealed tube was added a solution of4-(1-[[5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylphenyl]carbonyl]piperidin-4-yl)benzonitrile(compound 258.2, 83.5 mg, 0.200 mmol, 1.00 equiv) in 1,4-dioxane (5 mL).Azetidine hydrochloride (93.0 mg, 0.990 mmol, 5.00 equiv) was added tothe reaction in portions. Potassium carbonate (276 mg, 2.00 mmol, 10.0equiv) was also added to the above mixture. The resulting solution wasstirred overnight at 105° C. behind a blast shield, then cooled to rt.The reaction was quenched with 20 mL of water. The mixture was extractedwith 30 mL of ethyl acetate and the organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theproduct (80 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, water with 50 mL NH₄CO₃ and CH₃CN (41.0% CH₃CN upto 43.0% in 8 min, up to 100.0% in 2 min, down to 41.0% in 2 min);Detector, Waters 2489 254&220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 18.0 mg (20%) of the titlecompound as a white solid. m/z (ES+) 455 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.68 (d, J=6.3 Hz, 2H), 7.48 (d, J=5.7 Hz, 2H), 7.24 & 7.13 (2singlets, amide rotamers, Ar—H, 1H), 6.52 (s, 1H), 4.91-7.77 (m, 1Hpartially obscured by water peak), 3.81-3.67 (m, 1H), 3.68 (t, J=5.6 Hz,4H), 3.32-3.18 (m, 1H), 3.05-1.91 (m, 2H), 2.84 (q, J=5.8 Hz, 2H),2.45-2.19 (m, 5H), 2.09-1.91 (m, 1H), 1.91-1.49 (m, 3H), 1.39 (t, J=5.7Hz, 3H).

Compound 259.4-(1-(5-(5-Ethyl-4H-1,2,4-triazol-3-yl)-2-methyl-4-(methylthio)benzoyl)piperidin-4-yl)benzonitrile

To a round-bottom flask was added a solution of4-(1-(5-(5-ethyl-4H-1,2,4-triazol-3-yl)-4-fluoro-2-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 258.2, 20 mg, 0.050 mmol, 1.0 equiv) in N,N-dimethylformamide(3 mL). Sodium thiomethoxide (70 mg, 0.10 mmol, 2.0 equiv) was added tothe reaction. The resulting mixture was stirred for 15 h at 110° C. inan oil bath, and then cooled to ambient temperature and quenched with100 mL of ice water. The mixture was extracted with 50 mL of ethylacetate and the combined organic layers were washed with 2×50 mL ofbrine, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The product (50 mg) was further purified by Prep-HPLCwith the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA andCH₃CN (37% CH₃CN up to 49% in 7 min, up to 100% in 3 min, down to 37% in2 min); Detector, Waters 2489 254&220 nm. The fractions containing purecompound were combined and lyophilized to yield 4 mg (19%) of the titlecompound as a white solid. m/z (ES+) 446 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.69 (d, J=8.4 Hz, 2H), 7.61-7.43 (m, 3H), 7.35 (br s, 1H),˜4.85 (1H partially obscured by water peak), 3.77-3.60 (m, 1H), ˜3.3 (1Hpartially obscured by methanol solvent peak), 3.08-2.94 (m, 2H), 2.91(q, J=7.7 Hz, 2H), 2.51 (s, 3H), 2.47 & 2.37 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.97 (m, 1H), 1.88-1.55 (m, 3H), 1.40 (t,3H).

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compound5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-N,4-dimethylbenzamide(compound 254):

Cmpnd m/z # Compound Name Compound Structure (ES+) 260 5-(4-(4-methoxy-phenyl)piperidine- 1-carbonyl)-2-methyl- N-(6-(pyrrolidin-1-yl)pyridin-3- yl)benzamide

499 (M + H)⁺ 261 5-(4-(4-cyano- phenyl)piperidine- 1-carbonyl)-2-methyl-N-((tetra- hydrofuran-2- yl)methyl)benzamide

432 (M + H)⁺ 262 5-(4-(4-cyano- phenyl)piperidine-1- carbonyl)-2-methyl-N-(tetrahydrofuran- 3-yl)benzamide

418 (M + H)⁺ 263 3-(4-(4-cyano- phenyl)piperidine-1- carbonyl)-N-(6-(pyrrolidin-1-yl) pyridin-3- yl)benzamide

480 (M + H)⁺ 264 5-(4-(4-cyano- phenyl)piperidine- 1-carbonyl)-2-methyl-N-(piperidin- 4-ylmethyl)benzamide

445 (M + H)⁺ 265 5-(4-(4-cyano- phenyl)piperidine- 1-carbonyl)-2-methyl-N-((1-methyl- piperidin-4-yl) methyl)benzamide

459 (M + H)⁺ 266 5-(4-(4-cyano- phenyl)piperidine- 1-carbonyl)-2-methyl-N-((tetrahydrofuran- 3-yl)methyl)benzamide

432 (M + H)⁺ 267 2-methyl-5-(4-(pyridin- 4-yl)piperidine-1-carbonyl)-N-(6- (pyrrolidin-1-yl) pyridin-3- yl)benzamide

470 (M + H)⁺ 268 5-(4-(4-cyano- phenyl)piperidine- 1-carbonyl)-N-(6-((2-hydroxyethyl)(methyl) amino)pyridin-3-yl)-2- methylbenzamide

499 (M + H)⁺ 269 5-(4-(4-cyano- phenyl)piperidine-1- carbonyl)-N-(6-(3-hydroxyazetidin-1- yl)pyridin-3-yl)-2- methylbenzamide

497 (M + H)⁺ 270 5-(4-(4-cyano- phenyl)piperidine-1- carbonyl)-2-methyl-N-(6-(4-methyl- piperazin-1-yl)pyridin- 3-yl)benzamide

524 (M + H)⁺

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 27,38, and 211:

Preparation similar to Cmpnd compound #(s) # Compound Name CompoundStructure [m/z (ES+)] 271 4-(1-(4-methyl-3- (6-(4-methyl-piperazin-1-yl)-3H- imidazo[4,5-c]pyridin- 2-yl)benzoyl)piperi-din-4-yl)benzonitrile

 27 [520 (M + H)⁺] 272 4-(1-(3-(6-(3-hydroxy- azetidin-1-yl)-3H-imidazo[4,5-c]pyridin- 2-yl)-4-methyl- benzoyl)piperidin-4-yl)benzonitrile

 27 [493 (M + H)⁺] 273 4-(1-(3-(6-((2-hydroxy- ethyl)(methyl)amino)-3H-imidazo[4,5-c] pyridin-2-yl)-4- methylbenzoyl)piperi-din-4-yl)benzonitrile

 27 [495 (M + H)⁺] 274 4-(1-(3-(5-isopropyl- 4H-1,2,4-triazol-3-yl)-4-methylbenzoyl)piperi- din-4-yl)benzonitrile

 38 [414 (M + H)⁺] 275 4-(1-(3-(5-ethyl-4H- 1,2,4-triazol-3-yl)-4-methylbenzoyl)piperi- din-4-yl)benzonitrile

 38 [400 (M + H)⁺] 276 (S)-4-(1-(4-methyl-3- (5-((tetrahydrofuran-3-yl)amino)-4H-1,2,4- triazol-3-yl)benzoyl) piperidin-4-yl) benzonitrile

211 [457 (M + H)⁺] 277 (R)-4-(1-(4-methyl-3- (5-((tetrahydrofuran-3-yl)amino)-4H-1,2,4- triazol-3-yl)benzoyl) piperidin-4-yl) benzonitrile

211 [457 (M + H)⁺] 278 (R)-4-(4-fluoro-1-(4- methyl-3-(5-((tetrahydro-furan-3-yl)amino)-4H- 1,2,4-triazol-3-yl) benzoyl)piperidin-4-yl)benzonitrile

211 [475 (M + H)⁺] 279 4-(1-(2,4-dimethyl-5- (5-((tetrahydrofuran-3-yl)amino)-4H-1,2,4- triazol-3-yl) benzoyl)piperidin-4- yl)benzonitrile

211 [471 (M + H)⁺]

Compound 280.1.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicotinoylhydrazinecarboxamide

A solution of 4-(1-(3-Amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile(compound 121.1, 0.1 g, 0.31 mmol) and triethyl amine (0.09 ml, 0.62mmol) in DCM (5 ml) was added to a solution of phosgene (20% in toluene,0.31 ml, 0.62 mmol) in DCM (5 ml) at 0° C. After the resulting reactionmixture was stirred at room temperature for 1.5 hours, all solvents wereremoved under reduced pressure. The residue was dried under high-vacuumfor 30 minutes then was re-dissolved in EtOH (5 ml).Isonicotinohydrazide (0.05 g, 0.34 mmol) was added. The mixture washeated at 80° C. over night. The ethanol was removed and the residue waspurified using prep.-TLC (10% MeOH in DCM) to give the product as alight brown solid. Yield: 0.14 g, 93%. m/z (ES+) 483.2 (M+H)⁺.

Compound 280.4-(1-(4-Methyl-3-(5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution ofN-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-2-isonicotinoylhydrazinecarboxamide(compound 280.1, 0.14 g, 0.29 mmol) and PPh₃ (0.09 g, 0.35 mmol) in DCM(10 ml) was added triethyl amine (0.061 ml, 0.43 mmol) followed withCCl₄ (0.08 ml, 0.87 mmol). The mixture was refluxed for 3 hours. TLC andLCMS showed that the reaction was complete. The mixture was cooled toroom temperature, diluted with DCM (100 ml), and washed with water (20ml). The organic layer was dried with Na₂SO₄, concentrated and purifiedusing prep.-TLC (5% MeOH in CH₂Cl₂) to yield 54 mg (42%) of a whitesolid. m/z (ES+) 465.0 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (br,1H), 8.77 (d, 2H), 7.92 (s, 1H), 7.81-7.73 (m, 4H), 7.50 (d, 2H), 7.33(d, 1H), 7.14 (d, 1H), 4.64 (m, 1H), 3.81 (m, 1H), 3.17 (m, 1H),3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.95-1.57 (m, 4H).

Compound 281.1.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide

To a solution of4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (121.1, 0.1 g,0.32 mmol) in DMF (3 ml) was added 1,1′-thio-CDI (0.056 g, 0.32 mmol).The mixture was stirred at room temperature for 3 hours. LCMS showed thereaction was complete. The mixture was carried to the next step in onepot without work up or purification. m/z (ES+) 430 (M+H)⁺.

Compound 281.2.1-(4-Aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)thiourea

To a solution ofN-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)-1H-imidazole-1-carbothioamide(281.1) in DMF continued from the prior step was addedpyridine-3,4-diamine (0.034, 0.32 mmol). The mixture was stirred at roomtemperature for 3 hours. LCMS showed the reaction was complete. Thereaction was carried to the next step without workup or purification.m/z (ES+) 471 (M+H)⁺.

Compound 281.4-(1-(3-((1H-Imidazo[4,5-c]pyridin-2-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of1-(4-aminopyridin-3-yl)-3-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)thiourea(281.2) in DMF continued from the prior step was added EDCI (0.12 g,0.64 mmol). The mixture was stiffed at room temperature overnight. TheDMF was removed under high vacuum and the residue was purified usingprep.-TLC (5% MeOH in EtOAc) to yield 76 mg (56% for 3 steps) of a whitepowder. m/z (ES+) 437 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (br, 1H),8.48 (s, 1H), 8.40 (s, 1H), 8.08 (d, 1H), 7.78 (d, 2H), 7.53 (d, 2H),7.29 (d, 2H), 7.05 (d, 1H), 4.65 (m, 1H), 3.91 (m, 1H), 3.17 (m, 1H),3.04-3.72 (m, 2H), 2.36 (s, 3H), 1.97-1.60 (m, 4H).

Compound 282.1.N-((5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothioyl)isobutyramide

Into around-bottom flask, was placed a solution of NH₄SCN (72 mg, 0.95mmol, 2.00 equiv) in acetone (10 mL). A solution of 2-methylpropanoylchloride (50 mg, 0.47 mmol, 1.00 equiv) in acetone was added (5 mL)dropwise at 25° C. and the reaction was stirred overnight at 40° C. inan oil bath. To this was added4-(1-(3-amino-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound121.1, 150 mg, 0.42 mmol, 1.00 equiv) at 25° C. The resulting solutionwas stiffed for 2 h at 25° C., then concentrated under reduced pressure.The residue was diluted with 100 mL of ethyl acetate. The organic layerwas washed with 2×30 mL of brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with dichloromethane/methanol (20:1) aseluent to furnish 150 mg (64%) of the title compound as a brown oil.

Compound 282.4-(1-(3-((5-Isopropyl-4H-1,2,4-triazol-3-yl)amino)-4-methylbenzoyl)piperidin-4-yl)benzonitrileInto a 10-mL sealed tube, was placed a solution ofN-((5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-methylphenyl)carbamothioyl)isobutyramide(compound 282.1, 200 mg, 0.40 mmol, 1.00 equiv, 90%) in ethanol (3 mL).NH₂NH₂HCl (234 mg, 2.23 mmol, 5.00 equiv) and potassium carbonate (185mg, 1.34 mmol, 3.00 equiv) were added to the reaction. The resultingsolution was stirred overnight at 80° C. in an oil bath behind a blastshield. After cooling to ambient temperature, the mixture wasconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water. The organic phase was washed with brine, dried(Na₂SO₄), and concentrated. The crude product (˜50 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-006(Waters)):Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with0.05% TFA and CH₃CN (hold 5.0% CH₃CN in 2 min, up to 30.0% in 1 min, upto 60.0% in 12 min, up to 100.0% in 1 min); Detector, UV 254/220 nm. Thefractions containing pure compound were combined and lyophilized toyield 10.3 mg (6%) of the title compound as a white solid. m/z (ES+) 429(M+H)⁺.

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 280,121, 281, and 282:

Preparation similar to Cmpnd compound #(s) # Compound Name CompoundStructure [m/z (ES+)] 283 4-(1-(4-methyl- 3-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2- yl)amino)benzoyl) piperidin-4-yl) benzonitrile

280 [465 (M + H)⁺] 284 4-(1-(3-((5-ethyl- 1,3,4-oxadiazol-2-yl)amino)-4- methylbenzoyl) piperidin-4- yl)benzonitrile

280 [416 (M + H)⁺] 285 4-(1-(3-((1H- imidazo[4,5- b]pyridin-2-yl)amino)-4-methyl- benzoyl)piperidin- 4-yl)benzonitrile

281 [437 (M + H)⁺] 286 4-(1-(3-((1H- imidazol-2-yl) amino)-4-methyl-benzoyl)piperidin- 4-yl)benzonitrile

281 [386 (M + H)⁺] 287 4-(1-(3-((5- (dimethylamino)- 1H-imidazo[4,5-b]pyridin-2-yl) amino)-4-methyl- benzoyl)piperidin- 4-yl)benzonitrile

281 [480 (M + H)⁺] 288 4-(1-(3-((5-(iso- butylamino)-1H-imidazo[4,5-b]pyridin- 2-yl)amino)-4-methyl- benzoyl)piperidin-4-yl)benzonitrile

281 [508 (M + H)⁺] 289 4-(1-(3-((5-(iso- propylamino)-1H-imidazo[4,5-b]pyridin- 2-yl)amino)-4-methyl- benzoyl)piperidin-4-yl)benzonitrile

281 [494 (M + H)⁺] 290 5-((5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)amino)-N- isopropylnicotinamide

121 [482 (M + H)⁺] 291 2-((5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)amino)-N- cyclopropyliso- nicotinamide

121 [480 (M + H)⁺] 292 6-((5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)amino)-N- cyclopropyl- nicotinamide

121 [480 (M + H)⁺] 293 2-((5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)amino)-N- ethylisonicotinamide

121 [468 (M + H)⁺] 294 6-((5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)-2-methyl- phenyl)amino)-N- ethylnicotinamide

121 [468 (M + H)⁺] 295 4-(1-(4-methyl-3- ((4-(4-methyl- piperazine-1-carbonyl)pyridin-2- yl)amino)benzoyl) piperidin-4- yl)benzonitrile

121 [523 (M + H)⁺] 296 4-(1-(3-((5-ethyl-4H- 1,2,4-triazol-3-yl)amino)-4-methyl- benzoyl)piperidin- 4-yl)benzonitrile

282 [415 (M + H)⁺]

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 26,43, 48, 50, 51, 64, and 80:

Preparation similar to Cmpnd compound #(s) # Compound Name CompoundStructure [m/z (ES+)] 297 1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1- carbonyl)-2-methyl- phenyl)-3- isobutylurea

64 [437 (M + H)⁺] 298 N-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)-2-methyl- phenyl)pyrrolidine- 1-carboxamide

50 and 64 [418 (M + H)⁺] 299 N-(5-(4-(6-cyano- pyridin-3-yl)piperidine-1-carbonyl)-2-methyl- phenyl)pyrrolidine- 1-carboxamide

51 and 64 [418 (M + H)⁺] 300 1-(5-(4-(6-cyano- pyridin-3-yl)piperidine-1-carbonyl)-2-methyl- phenyl)-3-(2- methoxyethyl)urea

51 and 64 [422 (M + H)⁺] 301 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)-2-methyl- phenyl)-3-(2- methoxyethyl)urea

50 and 64 [422 (M + H)⁺] 302 1-(5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)pyridazin- 3-yl)-3-(2-methoxy- ethyl)urea

64 [409 (M + H)⁺] 303 N-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)-2-methyl- phenyl)-6-(ethyl- amino)nicotinamide

50 [469 (M + H)⁺] 304 6-(azetidin-1-yl)-N- (5-(4-(5-cyanopyridin-2-yl)piperidine-1- carbonyl)-2-methyl- phenyl)nicotinamide

50 [481 (M + H)⁺] 305 1-(5-(4-(4-cyano- phenyl)piperidine-1-carbonyl)pyridazin-3- yl)-3-isobutylurea

64 [407 (M + H)⁺] 306 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- isopropylurea

50 and 64 [406 (M + H)⁺] 307 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- cyclobutylurea

50 and 64 [418 (M + H)⁺] 308 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- cyclopentylurea

50 and 64 [432 (M + H)⁺] 309 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- (oxetan-3-yl)urea

50 and 64 [420 (M + H)⁺] 310 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- (tetrahydro-2H-pyran-4-yl)urea

50 and 64 [448 (M + H)⁺] 311 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- (tetrahydro-2H-pyran-3-yl)urea

50 and 64 [448 (M + H)⁺] 312 6-(azetidin-1-yl)-N- (5-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1- carbonyl)-2-methyl- phenyl)nicotinamide

43 [498 (M + H)⁺] 313 1-(5-(4-(5-cyano- pyridin-2-yl)piperidine-1-carbonyl)- 2-methylphenyl)-3- (tetrahydrofuran- 3-yl)urea

50 and 64 [434 (M + H)⁺] 314 2-(azetidin-1-yl)-N- (5-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1- carbonyl)-2-methyl- phenyl)pyrimidine-5-carboxamide

43 [499 (M + H)⁺] 315 1-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoropiperidine-1- carbonyl)-2-methyl- phenyl)-3-(tetrahydro-furan-3-yl)urea

26 and 64 [452 (M + H)⁺] 316 (S)-1-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoropiperidine-1- carbonyl)-2-methyl- phenyl)-3-(tetrahydro-furan-3-yl)urea

26 and 64 [452 (M + H)⁺] 317 1-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoropiperidine-1- carbonyl)-2-methyl- phenyl)-3-(tetrahydro-2H-pyran-4-yl)urea

26 and 64 [466 (M + H)⁺] 318 1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-3- (tetrahydrofuran-3- yl)urea

64 [451 (M + H)⁺] 319 (S)-1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-3- (tetrahydrofuran-3- yl)urea

64 [451 (M + H)⁺] 320 1-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoropiperidine-1- carbonyl)-2-methyl- phenyl)-3-(oxetan- 3-yl)urea

26 and 64 [438 (M + H)⁺] 321 1-(2-chloro-5-(4-(4- cyanophenyl)-4-fluoropiperidine-1- carbonyl)phenyl)-3- (tetrahydrofuran-3- yl)urea

26 and 64 [471 (M + H)⁺] 322 6-(azetidin-1-yl)-N- (5-(4-(5-cyano-pyridin-2-yl)-4-fluoro- piperidine-1- carbonyl)-2-methyl-phenyl)nicotinamide

26 and 43 [499 (M + H)⁺] 323 N-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoro-piperidine-1- carbonyl)-2-methyl- phenyl)-6-(isopropyl-amino)nicotinamide

26 and 43 [501 (M + H)⁺] 324 1-(5-(4-fluoro-4-(5- methoxypyridin-2-yl)piperidine-1- carbonyl)-2-methyl- phenyl)-3-(tetrahydro-furan-3-yl)urea

1, 11, and 64 [457 (M + H)⁺] 325 1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-3- ((1-methylpiperidin-4-yl)methyl)urea

64 [492 (M + H)⁺] 326 6-(azetidin-1-yl)-N- (2-methyl-5-(4-(pyridin-4-yl) piperidine-1-carbonyl) phenyl)nicotinamide

43 [492 (M + H)⁺] 327 1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-3- (piperidin-4- ylmethyl)urea

64 [492 (M + H)⁺] 328 6-(azetidin-1-yl)-N- (5-(4-(4-cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2-fluoro- phenyl)nicotinamide

43 [502 (M + H)⁺] 329 3-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-1-(2- methoxyethyl)-1-methylurea

64 [453 (M + H)⁺] 330 6-(azetidin-1-yl)-N- (5-(4-(4-cyanophenyl)-4-fluoropiperidine- 1-carbonyl)-2- (trifluoromethyl) phenyl)nicotinamide

43 [552 (M + H)⁺] 331 6-(azetidin-1-yl)-N- (5-(4-(4-cyanophenyl)-4-fluoropiperidine-1- carbonyl)-2-methoxy- phenyl)nicotinamide

43 [514 (M + H)⁺] 332 (S)-1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-methylphenyl)-3- ((tetrahydrofuran-2-yl)methyl)urea

64 [465 (M + H)⁺] 333 (R)-1-(2-chloro-5-(4- (4-cyanophenyl)-4-fluoropiperidine-1- carbonyl)phenyl)-3- (tetrahydrofuran-3- yl)urea

64 [471 (M + H)⁺] 334 N-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2,4-dimethyl- phenyl)-6-(piperazin-1-yl)nicotinamide

43 [541 (M + H)⁺] 335 (R)-1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-ethyl-4-methyl- phenyl)-3-(tetrahydro-furan-3-yl)urea

64 [479 (M + H)⁺] 336 (R)-tetrahydrofuran- 3-yl (3-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1-carbonyl)- 4-methylphenyl) carbamate

80 [452 (M + H)⁺] 337 1-acetylpyrrolidin-3- yl (3-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1-carbonyl)- 4-methylphenyl) carbamate

80 [493 (M + H)⁺] 338 (R)-1-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-ethyl-4-methyl- phenyl)-3-((tetrahydro-furan-2-yl)methyl)urea

64 [493 (M + H)⁺] 339 (S)-tetrahydrofuran- 3-yl (5-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1-carbonyl)- 2-methylphenyl) carbamate

80 [452 (M + H)⁺] 340 6-(azetidin-1-yl)-N- (5-(4-(4-cyanophenyl)-4-fluoropiperidine-1- carbonyl)-2-ethyl-4- methylphenyl) nicotinamide

43 [526 (M + H)⁺] 341 N-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 4-ethyl-2-methyl- phenyl)-6-((2-methoxyethyl)methyl) amino)nicotinamide

43 and 48 [558 (M + H)⁺] 342 N-(5-(4-(4-cyano- phenyl)-4-fluoro-piperidine-1-carbonyl)- 2-ethyl-4-methylphenyl)- 6-(isopropylamino)nicotinamide

43 [528 (M + H)⁺] 343 N-(5-(4-(5-cyano- pyridin-2-yl)-4-fluoro-piperidine-1-carbonyl)- 2,4-dimethylphenyl)-6- morpholinonicotinamide

26 and 43 [543 (M + H)⁺] 344 (R)-tetrahydrofuran- 3-yl (5-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1-carbonyl)- 4-ethyl-2-methyl-phenyl)carbamate

48 and 80 [480 (M + H)⁺] 345 (S)-tetrahydrofuran- 3-yl (5-(4-(4-cyano-phenyl)-4-fluoro- piperidine-1-carbonyl)- 4-ethyl-2-methyl-phenyl)carbamate

48 and 80 [480 (M + H)⁺]

Compound 346.1. 2-(1-Benzyl-4-hydroxypiperidin-4-yl)-5-bromobenzoicacid.

To a stirred solution of 2,5-dibromobenzoic acid (27.8 g, 100 mmol, 1.00equiv) in THF/Et₂O (450/50 mL) under nitrogen at −78° C. was addeddropwise n-BuLi (2.5M) (88 mL, 2.20 equiv). After 2 h at −78° C., wasadded 1-benzylpiperidin-4-one (26.5 g, 140 mmol, 1.40 equiv). Theresulting solution was stirred for 0.5 h at −78° C. and then warmed toroom temperature, and stiffed overnight. The reaction was quenched bycarefully adding 200 mL of water. The pH of the mixture was adjusted to2-3 with hydrogen chloride (aq., 2 M). The aqueous phase was extractedwith 3×500 mL of ethyl acetate and 3×500 mL of tetrahydrofuran. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to yield 38.9 g (crude) of the titlecompound as a yellow solid.

Compound 346.2.1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidin]-3-one

Into a round-bottom flask, was placed a solution of crude compound 346.1(38.9 g, 100 mmol, 1.00 equiv) in tetrahydrofuran (800 mL). To this wasadded sulfuric acid (8 mL) dropwise. The resulting solution was stirredovernight at reflux in an oil bath. The pH value of the solution wasslowly adjusted to 10 with LiOH (aq.sat.). The aqueous phase wasextracted with 3×500 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:81:5) as eluent to furnish 8.00 g (22%)of the title compound as a white solid.

Compound 346.3.1′-Benzyl-5-bromo-3H-spiro[isobenzofuran-1,4′-piperidine]

To a solution of compound 346.2 (10.0 g, 26.9 mmol, 1.00 equiv) intetrahydrofuran (150 mL) under nitrogen at −10° C. was added dropwiseBH₃-THF (135 mL, 5.00 equiv). The resulting solution was stiffed for 30min at room temperature and then heated at reflux temperature overnight.After cooling to −10° C., hydrogen chloride (aq., 6 M, 60 mL) was addeddropwise at −10° C. The resulting solution was heated to reflux for 5 hin an oil bath. The reaction mixture was cooled and the pH of thesolution was adjusted to 10 with potassium hydroxide (aq., 1 M). Theaqueous phase was extracted with 2×200 mL of ethyl acetate and thecombined organic layers were washed with 2×300 mL of brine, dried oversodium sulfate, and concentrated under reduced pressure to yield 15.0 g(crude) of the tile compound as a yellow oil.

Compound 346.4.P-Benzyl-3H-spiro[isobenzofuran-1,4′-piperidine]-5-carbonitrile

Into a three neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of compound346.3 (12.0 g, 33.6 mmol, 1.00 equiv) in N,N-dimethylformamide (150 mL).Zn(CN)₂ (4.50 g, 38.5 mmol, 1.14 equiv) and Pd(PPh₃)₄ (4.00 g) wereadded to the reaction. The resulting solution was stiffed overnight at90° C. in an oil bath. The reaction mixture was cooled to rt, thenquenched with 200 mL of FeSO₄ (aq. sat.) and diluted with ethyl acetate.The resulting mixture was stirred vigorously then filtered throughcelite and washed with 1 M FeSO₄, water, and ethyl acetate. The layerswere separated and the aqueous phase was extracted with 2×200 mL ofethyl acetate. The combined organic layers were washed with 2×100 mL ofsodium chloride (aq. sat.), dried over sodium sulfate, and concentratedunder reduced pressure. The residue was purified using silica gel columnchromatography with petroleum ether/ethyl acetate (10:1˜5:1) as eluentto yield 9.12 g (89%) of the title compound as a yellow oil.

Compound 346.5. 3H-Spiro[isobenzofuran-1,4′-piperidine]-5-carbonitrile

To a solution of 346.4 (9.12 g, 30.0 mmol, 1.00 equiv) in DCE (150 mL)0° C. was added dropwise 1-chloroethyl chloroformate (8.52 g, 60.0 mmol,2.00 equiv). After stirring at ambient temperature for 30 min,triethylamine (9.09 g, 3.00 equiv) was carefully added to the mixture.The resulting solution was heated to reflux for 2 h in an oil bath, thenconcentrated under reduced pressure. The residue was dissolved in 100 mLof methanol and then heated to reflux for 1 h in an oil bath. Theresulting mixture was concentrated under reduced pressure and theresidue was taken up in water (100 mL). The pH of the mixture wasadjusted to 10 with sodium hydroxide (aqueous, 1 M). The aqueous phasewas extracted with 3×200 mL of ethyl acetate and the combined organiclayers were washed with 2×100 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethylacetate/methanol (100:0 to 3:1) as eluent to furnish 3.50 g (46%) of thetitle compound as a yellow solid.

Compound 346.N-(5-(5-Cyano-3H-spiro[isobenzofuran-1,4′-piperidin]-1′-ylcarbonyl)-2-methylphenyl)-6-(pyrrolidin-1-yl)nicotinamide

The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compound 346.5 was in placeof compound 11.2. m/z (ES+) 522 (M+H)⁺.

Compound 347.1. tert-Butyl4-(4-cyanophenyl)-2-oxopiperidine-1-carboxylate

Into a round-bottom flask, was placed a solution of tert-butyl4-(4-cyanophenyl)piperidine-1-carboxylate (compound 1.4, 515 mg, 1.80mmol, 1.00 equiv) in ethyl acetate (5 mL). A solution of NaIO₄ (963 mg,4.50 mmol, 2.50 equiv) in water (5 mL) and RuCl₃ (74.7 mg, 0.36 mmol,0.20 equiv) was carefully added. The resulting mixture was stirredovernight at room temperature. The solids were removed by filtration andthe filtrate was washed with 2×20 mL of water, dried over anhydroussodium sulfate, and concentrated under reduced pressure to yield 432 mg(80%) of the title compound as a light yellow oil.

Compound 347.2. 4-(2-Oxopiperidin-4-yl)benzonitrile

Into a round-bottom flask, was placed a solution of compound 347.1 (432mg, 1.44 mmol, 1.00 equiv) in ethyl acetate (10 mL). Hydrogen chloridegas was bubbled through the solution and the resulting mixture wasstirred for 0.5 h at room temperature. The solids were collected byfiltration, then dissolved in 50 mL of ethyl acetate. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure to yield 254 mg (88%) of the title compound as a white solid.

Compound 347.3.4-(6-Methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile.

Into a round-bottom flask, was placed a solution of4-(2-oxopiperidin-4-yl)benzonitrile

(347.2, 220 mg, 1.10 mmol, 1.00 equiv) in dichloromethane (10 mL).Trimethyloxonium tetrafluoroborate (244.2 mg, 1.65 mmol, 1.50 equiv) wasslowly added and the resulting mixture was stirred for 2 h at roomtemperature. The pH was carefully adjusted to 8 with sodium bicarbonate(aq.). The organic layer was washed with 2×20 mL of H₂O, dried overanhydrous sodium sulfate and concentrated under reduced pressure toyield 212 mg (90%) of the title compound as a white solid.

Compound 347.4. 3-Amino-4-methylbenzohydrazide

Into a round-bottom flask, was placed a solution of methyl3-amino-4-methylbenzoate (6.60 g, 40.0 mmol, 1.00 equiv) in ethanol (100mL). Hydrazine hydrate (10.0 g, 200 mmol, 5.00 equiv) was added to thereaction. The resulting solution was stirred for 2 h at 100° C. in anoil bath. After cooling to ambient temperature, the mixture wasconcentrated under reduced pressure. The residue was partitioned betweenwater and ethyl acetate (20 mL). The aqueous layer was extracted with4×20 mL of ethyl acetate and the combined organic layers were dried overanhydrous sodium sulfate, concentrated under reduced pressure, and driedunder high-vacuum to yield 4.60 g (70%) of the title compound as a brownsolid.

Compound 347.5.4-(3-(3-Amino-4-methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)benzonitrile

To a solution of4-(6-methoxy-2,3,4,5-tetrahydropyridin-4-yl)benzonitrile (compound347.3, 5.00 g, 23.36 mmol, 1.00 equiv) in 1,2-dichlorobenzene (100 mL)was added 3-amino-4-methylbenzohydrazide (compound 347.4, 4.63 g, 28.0mmol, 1.20 equiv). The resulting solution was stirred overnight at 150°C. in an oil bath. After cooling to ambient temperature, the resultingmixture was purified using silica gel column chromatography withdichloromethane/methanol (1:0˜100:1) as eluent to furnish 2.40 g (31%)of the title compound as a white solid.

Compound 347.N-(5-(7-(4-Cyanophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-2-methylphenyl)-6-(isopropylamino)nicotinamide

The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compound 347.5 was in placeof compound 42.2. m/z (ES+) 492 (M+H)⁺.

Compound 348.1. 2-Hydroxy-6-methyl-5-nitronicotinic acid

To a solution of 2-hydroxy-6-methylnicotinic acid (14.0 g, 91.5 mmol,1.00 equiv) in sulfuric acid (conc.) (140 mL) at 0° C. was addeddropwise a solution of HNO₃ (12.0 g, 190 mmol, 2.00 equiv) in sulfuricacid (conc.) (10 mL). The resulting mixture was then stirred for 2 h at90° C., cooled to ambient temperature, and then quenched with 250 mL ofice water. The resulting solids were collected by filtration and driedin an oven under reduced pressure to yield 15.8 g (87%) of the titlecompound as a yellow solid.

Compound 348.2. Methyl 2-chloro-6-methyl-5-nitronicotinate

To a solution of 2-hydroxy-6-methyl-5-nitronicotinic acid (compound348.1, 15.0 g, 75.8 mmol, 1.00 equiv) in chlorobenzene (150 mL) werecarefully added phosphoryl trichloride (45.0 g, 296 mmol, 4.00 equiv)and N,N-dimethylformamide (1.5 mL, 0.10 equiv). The resulting mixturewas stirred for 2 h at 135° C., and then concentrated under reducedpressure. The residue was dissolved in 20 mL of DCM. To this was addedmethanol (20 mL) dropwise. The resulting solution was stirred for 3 h at25° C., and then concentrated under reduced pressure. To the residue wascarefully added 100 mL of water and the pH of the resulting mixture wasslowly adjusted to 8 with sodium bicarbonate (aq.). The aqueous phasewas extracted with 2×200 mL of ethyl acetate. The combined organiclayers were dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield 17.6 g (crude) of the title compound as ayellow solid.

Compound 348.3. Methyl 5-amino-6-methylnicotinate

A round-bottom flask, containing a solution of methyl2-chloro-6-methyl-5-nitronicotinate (12.8 g, 55.5 mmol, 1.00 equiv) inmethanol (120 mL) was purged with nitrogen. Triethylamine (15.0 g, 149mmol, 2.68 equiv) and palladium on carbon (1.30 g) were added. Afterfurther purging the flask with nitrogen, the atmosphere was changed tohydrogen and the resulting solution was stirred for 2 days at roomtemperature under atmospheric pressure. After purging the system withnitrogen, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:50-1:5) as eluent to furnish 3.50 g (38%) of the title compound as ayellow solid.

Compound 348.4. 5-Amino-6-methylnicotinic acid

Into a round-bottom flask, was placed a solution of methyl5-amino-6-methylnicotinate (5.00 g, 30.1 mmol, 1.00 equiv) and sodiumhydroxide (20 g) in MeOH/H₂O (80/200 mL). The resulting solution washeated at reflux overnight. After cooling to ambient temperature, themethanol was removed under reduced pressure. The pH of the remainingaqueous phase was adjusted to 4 with aqueous hydrogen chloride (2 M).The resulting mixture was then concentrated under reduced pressure toyield 5.00 g (crude) of the title compound as a yellow solid.

Compound 348.N-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2-methylpyridin-3-yl)-6-(pyrrolidin-1-yl)nicotinamide

The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 348.4 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES+) 495 (M+H)⁺.

Compound 349.1. 2-Bromo-5-methylpyridine 1-oxide

Into a round-bottom flask, was placed a solution of2-bromo-5-methylpyridine (10.0 g, 58.1 mmol, 1.00 equiv) indichloromethane (250 mL). mCPBA (15.0 g, 86.9 mmol, 1.50 equiv) wasadded in several batches at room temperature. The resulting solution wasstirred overnight at 30° C., then diluted with 50 mL of 2N sodiumhydroxide (aq.). The pH value of the solution was adjusted to 10 with 2Nsodium hydroxide (aq.). The aqueous phase was extracted with 3×100 mL ofdichloromethane and the combined organic layers were dried overanhydrous magnesium sulfate and concentrated under reduced pressure toyield 11.0 g (91%) of 2-bromo-5-methylpyridin-1-ium-1-olate as a yellowsolid.

Compound 349.2. 2-Bromo-5-methyl-4-nitropyridine 1-oxide

Into a round-bottom flask, was placed HNO₃ (15 mL), sulfuric acid (20mL). To this was added compound 349.1 (11.0 g, 52.7 mmol, 1.00 equiv,90%) in several batches at room temperature. The resulting mixture wasstirred overnight at 100° C., then cooled to ambient temperature andquenched with 50 mL of ice water. The pH was slowly adjusted to 2-3 withsodium hydroxide (aq. 2 M) and the resulting mixture was extracted with3×50 mL of dichloromethane. The combined organic layers were dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified using silica gel column chromatography with ethylacetate/petroleum ether (1:2) as eluent to furnish 3.00 g (23%) of thetitle compound as a yellow solid.

Compound 349.3. Methyl 4-amino-5-methylpicolinate

Into a 250-mL autoclave (30 atm, CAUTION: Carry out behind a blastshield) purged and maintained with an inert atmosphere of nitrogen, wasplaced a solution of 2-bromo-5-methyl-4-nitropyridine 1-oxide (compound349.2, 3.00 g, 12.9 mmol, 1.00 equiv) in methanol (120 mL).Triethylamine (2.60 g, 25.7 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (600 mg,0.82 mmol, 0.06 equiv) were added to the reaction. The autoclave waspurged and the mixture was then stirred overnight under 30 atm of CO (g)at 90° C. After cooling to ambient temperature, the mixture wasconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate:methanol (20:1) aseluent to furnish 1.50 g (67%) of methyl4-amino-5-methylpyridine-2-carboxylate as a yellow solid.

Compound 349.4. 4-Amino-5-methylpicolinic acid

A solution of methyl 4-amino-5-methylpicolinate (compound 349.3, 1.50 g,8.12 mmol, 1.00 equiv, 90%) and 5N sodium hydroxide (aq., 15 mL) inmethanol (15 mL) was stiffed overnight at room temperature, thenconcentrated under reduced pressure. The residue was diluted with 20 mLof H₂O and the pH was adjusted to 3-4 with 2 M aqueous hydrogenchloride. The resulting precipitate was collected by filtration anddried to yield 0.8 g (58%) of the title compound as a yellow solid.

Compound 349.N-(2-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-5-methylpyridin-4-yl)-6-(isopropylamino)nicotinamide

The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 349.4 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES+) 483 (M+H)⁺.

Compound 350.1. 2-Bromo-3-methylpyridine 1-oxide

The title compound was prepared (8.00 g, 85%) using a procedure similarto that used for the preparation of compound 349.1 and using2-bromo-3-methylpyridine (8.60 g) in place of 2-bromo-5-methylpyridine.

Compound 350.2. 6-Bromo-5-methylpicolinonitrile

To a solution of 2-bromo-3-methylpyridine 1-oxide (compound 350.1, 5.65g, 30.1 mmol, 1.00 equiv) in acetonitrile (50 mL) were addedtriethylamine (6.10 g, 60.3 mmol, 2.00 equiv) and TMSCN (8.90 g, 3.00equiv). The resulting solution was heated to reflux and stiffedovernight in an oil bath, then cooled to ambient temperature andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:5) as eluent to yield 2.00 g (34%) of the title compound as a yellowsolid.

Compound 350.3. 6-Bromo-5-methylpicolinimidamide

Into a 50-mL sealed tube, was placed a solution of6-bromo-5-methylpicolinonitrile (compound 350.2, 900 mg, 4.57 mmol, 1.00equiv) in methanol (40 mL). NH₃ (g) was bubbled through the solution andthe resulting solution was stirred overnight at 95° C. in an oil bathbehind a blast shield. After cooling to ambient temperature, the mixtureconcentrated under reduced pressure to yield 800 mg (82%) of the titlecompound as a light brown solid.

Compound 350.4. 6-Amino-5-methylpicolinamide

Into a 50-mL sealed tube, was placed a solution of6-bromo-5-methylpicolinimidamide (compound 350.3, 800 mg, 3.74 mmol,1.00 equiv) and CuSO₄ (80 mg) in NH₃.H₂O (40 mL). The resulting mixturewas stirred overnight at 80° C. behind a blast shield. After cooling toambient temperature, the mixture was then extracted with 2×50 mL ofethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated under reduced pressure to yield 750 mg(crude) of the title compound as a brown solid.

Compound 350.5. 6-Amino-5-methylpicolinic acid hydrochloride

Into around-bottom flask was placed a solution of6-amino-5-methylpicolinamide (compound 350.4, 500 mg, 3.31 mmol, 1.00equiv) in hydrogen chloride (conc., 15 mL). The resulting solution washeated to reflux overnight in an oil bath, then concentrated underreduced pressure to yield 600 mg (crude) of the title compound as alight yellow solid.

Compound 350.N-(6-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-3-methylpyridin-2-yl)-6-(isopropylamino)nicotinamide

The title compound was prepared using procedures similar to those usedfor the preparation of compound 43 and using compounds 350.5 and 1.5 inplace of 5-amino-2,4-dimethylbenzoic acid and compound 11.2respectively. m/z (ES+) 483 (M+H)⁺.

Compound 351.1. Methyl 5-nitro-1H-pyrazole-3-carboxylate

Into a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of5-nitro-1H-pyrazole-3-carboxylic acid (5.00 g, 31.9 mmol, 1.00 equiv) inmethanol (150 mL). To this was added thionyl chloride (5.60 g, 47.8mmol, 1.50 equiv) dropwise at 0° C. The resulting solution was stirredfor 18 h at 30° C. in an oil bath, then concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:30-1:10) as eluentto furnish 5.00 g (78%) of the title compound as a brown solid.

Compound 351.2 and 351.3. Methyl1-methyl-5-nitro-1H-pyrazole-3-carboxylate and methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate

Into a round-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl5-nitro-1H-pyrazole-3-carboxylate (3.00 g, 17.5 mmol, 1.00 equiv) inN,N-dimethylformamide (30 mL). Potassium carbonate (4.84 g, 35.0 mmol,2.00 equiv) and CH₃I (2.98 g, 21.0 mmol, 1.20 equiv) were added at 0° C.The resulting solution was stirred for 2 h at 40° C. in an oil bath.After cooling to ambient temperature, the solids were removed byfiltration followed by the addition of 120 mL of ice water. The mixturewas extracted with 3×100 mL of ethyl acetate and the combined organiclayers were dried over anhydrous sodium sulfate and concentrated undervacuum. The crude product was purified by re-crystallization from ether.This resulted in 1.10 g (34%) of methyl1-methyl-3-nitro-1H-pyrazole-5-carboxylate as a white solid. m/z (ES+)186 (M+H)⁺. ¹H-NMR, (300 MHz, DMSO-d₆, ppm): ˜7.57 (s, 1H), 4.22 (s,3H), 3.91 (s, 3H). The filtrate was concentrated under vacuum and thecrude product (2 g) was purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (10% CH₃CN up to56.5% in 10 min); Detector, uv 254 nm. The fractions containing purecompound were combined and concentrated to yield 470 mg (15%) of methyl1-methyl-5-nitro-1H-pyrazole-3-carboxylate as a white solid. m/z (ES+)186 (M+H)⁺. ¹H-NMR, (300 MHz, DMSO-d₆, ppm): □□ 7.64 (1H, s), 4.24 (3H,s), 3.87 (3H, s).

Compound 351.4. Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate

To a solution of methyl 1-methyl-5-nitro-1H-pyrazole-3-carboxylate(351.2, 0.48 g, 2.60 mmol) in MeOH (15 ml) under nitrogen was addedpalladium on carbon (10%, 0.25 g). The flask was further degassed withnitrogen and filled with H₂ through a balloon. The mixture was stirredat room temperature for 1.5 hours. After purging the system withnitrogen, the reaction mixture was filtered through a Celite cake andconcentrated to give 363 mg (90%) of a white solid. m/z (ES+) 156(M+H)⁺.

Compound 351.5. Methyl5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate

To a solution of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate(compound 351.4, 0.088 g, 0.57 mmol) in THF (5 ml) was added triphosgene(0.084 g, 0.28 mmol) followed by DIEA (0.2 ml, 1.14 mmol). After themixture was stirred at room temperature for 2 hours, isobutyl amine(0.225 ml, 2.28 mmol) was added. The resulting mixture was stirred atroom temperature over night. The mixture was partitioned between waterand EtOAc. The EtOAc layer was washed with 1 M aqueous NaH₂PO₄ solutionfollowed by brine, dried with Na₂SO₄, and concentrated to give 120 mg(83%) of a light yellow solid. m/z (ES+) 255 (M+H)⁺.

Compound 351.6. 5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylicacid

To a solution of methyl5-(3-isobutylureido)-1-methyl-1H-pyrazole-3-carboxylate (compound 351.5,0.12 g, 0.47 mmol) in MeOH (5 ml) was added 1 M LiOH in H₂O (1.42 ml,1.42 mmol). The mixture was stirred at room temperature for 5 hours. TLCshowed the reaction was complete. The mixture was acidified to pH 3-4 at0° C. and then was extracted with EcOAc (2×50 ml). The combined organiclayers were dried with Na₂SO₄, filtered, and concentrated to give 110 mg(100%) of a clear oil. m/z (ES+) 241 (M+H)⁺.

Compound 351.1-(3-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-1-methyl-1H-pyrazol-5-yl)-3-isobutylurea

A solution of 5-(3-Isobutylureido)-1-methyl-1H-pyrazole-3-carboxylicacid (compound 351.6, 0.11 g, 0.46 mmol), 4-(piperidin-4-yl)benzonitrileHCl salt (compound 1.5, 0.097 g, 0.4 6 mmol), EDCI (0.090 g, 0.51 mmol),HOBT (0.065 g, 0.51 mmol, with 20% H₂O) and DIEA (0.22 ml, 1.38 mmol) inDMF (5 ml) was stirred at room temperature overnight. The reactionmixture was then diluted with 50 ml of ethyl acetate and washed with2×20 ml of brine. The organic phase was dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue waspurified using prep.-TLC and developed using neat ethyl acetate to yield25 mg of the title compound as an off-white solid. m/z (ES+) 409 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ8.46 (s, 1H), 7.76 (d, 2H), 7.49 (d, 2H),6.48 (t, 1H), 6.37 (s, 1H), 4.84 (d, 1H), 4.63 (d, 1H), 3.65 (s, 3H),3.14 (m, 1H), 2.92 (t, 3H), 2.79 (m, 2H), 1.85 (m, 1H), 1.67 (m, 1H),1.57 (m, 2H), 0.87 (d, 6H).

The compounds in the following table were prepared using standardchemical manipulations, readily available starting materials, andprocedures similar to those used for the preparation of compounds 346,347, 348, 349, 350, and 351:

Preparation similar to compound Cmpnd Compound #(s) # name CompoundStructure [m/z (ES+)] 352 1-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-isobutylurea

346 and 64 [447 (M + H)⁺] 353 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl) pyrrolidine-1-carboxamide

346 and 64 [445 (M + H)⁺] 354 1-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-(2-methoxyethyl) urea

346 and 64 [449 (M + H)⁺] 355 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6-(isopropylamino) nicotinamide

346 [510 (M + H)⁺] 356 3-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-1- (2-methoxyethyl-1-methylurea

346 and 64 [463 (M + H)⁺] 357 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6-(4-methylpiperazin- 1-yl)nicotinamide

346 [551 (M + H)⁺] 358 N-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6- piperazin-1-yl)nicotinamide

346 [537 (M + H)⁺] 359 N-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6- ((2-methoxyethyl)(methyl)amino) nicotinamide

346 [540 (M + H)⁺] 360 N-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6- ((2-methoxyethyl)amino)nicotinamide

346 [526 (M + H)⁺] 361 N-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6- ((2-hydroxyethyl)amino)nicotinamide

346 [512 (M + H)⁺] 362 N-(5-(5-cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-6- ((2-hydroxyethyl)(methyl)amino) nicotinamide

346 [526 (M + H)⁺] 363 (S)-1-(5-(5- cyano-3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)-3- ((tetrahydrofuran-2-yl)methyl)urea

346 and 64 [475 (M + H)⁺] 364 1-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-3-isobutylurea

346, 348, and 64 [448 (M + H)⁺] 365 1-(5-(5- cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)-3-(1-methylpiperidin- 4-yl)urea

346 and 64 [488 (M + H)⁺] 366 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-6-(pyrrolidin- 1-yl)nicotinamide

346 and 348 [523 (M + H)⁺] 367 1-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-3-(2-methoxy- ethyl)urea

346, 348, and 64 [450 (M + H)⁺] 368 1-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)-3-((tetrahydrofuran- 3-yl)methyl)urea

346 and 64 [475 (M + H)⁺] 369 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-6-(isopropyl- amino)nicotinamide

346 and 348 [511 (M + H)⁺] 370 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-6-(dimethyl- amino)nicotinamide

346 and 348 [497 (M + H)⁺] 371 6-(azetidin-1-yl)- N-(5-(5-cyano-3H-spiro[isobenzo furan-1,4′- piperidin]-1′- ylcarbonyl)-2-methylpyridin-3- yl)nicotinamide

346 and 348 [509 (M + H)⁺] 372 N-(5-(5-cyano-3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylpyridin-3-yl)-6-((2-methoxy- ethyl)amino) nicotinamide

346 and 348 [527 (M + H)⁺] 373 N-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3- a]pyridin-3- yl)-2- methylphenyl)pyrrolidine-1- carboxamide

347 and 64 [427 (M + H)⁺] 374 1-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3- a]pyridin-3- yl)-2- methylphenyl)-3-(2-methoxyethyl) urea

347 and 64 [431 (M + H)⁺] 375 1-(5-(7-(4- cyanophenyl)- 5,6,7,8-tetrahydro- [1,2,4]triazolo [4,3- a]pyridin-3- yl)-2- methylphenyl)-3-isobutylurea

347 and 64 [429 (M + H)⁺] 376 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-3- isobutylurea

348 and 64 [420 (M + H)⁺] 377 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-3-(2- methoxyethyl) urea

348 and 64 [422 (M + H)⁺] 378 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)pyrrolidine- 1-carboxamide

348 and 64 [418 (M + H)⁺] 379 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-2- methylpyridin- 3-yl)-6-(isopropyl- amino)nicotinamide

348 [438 (M + H)⁺] 380 1-(5-(5-cyano- 3H- spiro[isobenzo furan-1,4′-piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 3-(piperidin- 4-yl)urea

348 and 64 [474 (M + H)⁺] 381 3-(5-(5-cyano- 3H- spiro[isobenzofuran-1,4′- piperidin]-1′- ylcarbonyl)-2- methylphenyl)- 1-methyl-1-((tetrahydrofuran- 3-yl)methyl)urea

348 and 64 [489 (M + H)⁺] 382 1-(2-(4-(4- cyanophenyl) piperidine-1-carbonyl)-5- methylpyridin- 4-yl)-3- (tetrahydrofuran- 3-yl)urea

349 and 64 [434 (M + H)⁺] 383 1-(6-(4-(4- cyanophenyl) piperidine-1-carbonyl)-3- methylpyridin- 2-yl)-3- (tetrahydrofuran- 3-yl)urea

321 and 64 [434 (M + H)⁺] 384 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)-6- (isobutylamino) nicotinamide

351 and 43 [486 (M + H)⁺] 385 N-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)-6- (isopropylamino) nicotinamide

351 and 43 [472 (M + H)⁺] 386 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1H- pyrazol-5-yl)-6- (isobutylamino) nicotinamide

351 and 43 [472 (M + H)⁺] 387 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1H- pyrazol-5-yl)-6- (isopropylamino) nicotinamide

351 and 43 [458 (M + H)⁺] 388 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 3-isobutylurea

351 and 64 [409 (M + H)⁺] 389 1-(5-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-3-yl)- 3-isopropylurea

351 and 64 [395 (M + H)⁺] 390 1-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-5-yl)- 3-isopropylurea

351 and 64 [395 (M + H)⁺] 391 N-(3-(4-(4- cyanophenyl) piperidine-1-carbonyl)-1- methyl-1H- pyrazol-5-yl)-6- (isobutylamino) nicotinamide

351 and 43 [486 (M + H)⁺]

Compound 392.1. 4-Cyclobutyl-5-formyl-2-methylbenzoic acid

Into a three neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution of4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 5.00 g, 12.7mmol, 1.00 equiv, 80%) in a solvent mixture of tetrahydrofuran and Et₂O(50/50 mL). This was followed by the addition of butyllithium (15 mL,2.50 equiv, 95%) dropwise with stirring at −78° C. To this was addedN,N-dimethylformamide (2.50 g, 32.5 mmol, 2.00 equiv). The resultingsolution was stirred for 1 h at −78° C. and then carefully quenched byslow addition of 50 mL of NH₄Cl (aq.). The pH was adjusted to 1-2 withhydrogen chloride (6 M). The resulting solution was diluted with 100 mLof ethyl acetate, then washed with 4×50 mL of brine. The organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified using silica gel column chromatography withethyl acetate/petroleum ether (1:1) as eluent to furnish 1.62 g (41%) of4-cyclobutyl-5-formyl-2-methylbenzoic acid as a white solid.

Compound 392.2.4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

Into a round-bottom flask, was placed a solution of4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg, 1.57mmol, 1.00 equiv, 70%) in N,N-dimethylformamide (8 mL). Compound 1.5(500 mg, 1.57 mmol, 1.00 equiv), EDC.HCl (860 mg, 4.26 mmol, 2.00 equiv,95%) and 4-dimethylaminopyridine (550 mg, 4.28 mmol, 2.00 equiv, 95%)were added to the reaction mixture. The resulting solution was stirredovernight at room temperature, and then diluted with 30 mL of ethylacetate. The resulting mixture was washed with 4×30 mL of brine, thendried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:2) as eluent toyield 560 mg (74%) of the title compound as a white solid.

Compound 392.4-(1-(4-Cyclobutyl-5-formyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile.Into around-bottom flask, was placed a solution of4-[1-[(4-cyclobutyl-5-formyl-2-methylphenyl)carbonyl]piperidin-4-yl]benzonitrile(392.2, 300 mg, 0.74 mmol, 1.00 equiv, 95%) in N,N-dimethylformamide (10mL). 3-Bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 210 mg, 1.17mmol, 1.00 equiv), ammonia (82 mg, 0.59 mmol, 3.00 equiv, 25% aq.), andNH₄OAc (270 mg, 2.81 mmol, 4.50 equiv, 80%) were added and the resultingmixture was stirred overnight at 130° C. under nitrogen. After coolingto room temperature, the mixture was diluted with 50 mL of ethylacetate, washed with 4×50 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography with ethyl acetate aseluent. The crude product (˜80 mg) was further purified by Prep-HPLCwith the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA andCH₃CN (26% CH₃CN up to 41% in 7 min, up to 100% in 3 min, down to 26% in2 min); Detector, Waters 2489 254&220 nm. The fractions containing purecompound were combined and lyophilized to yield 24.6 mg (7%) of thetitle compound as a white solid. m/z (ES+) 481 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.67 (d, J=7.8 Hz, 2H), 4.47 (d, J=8.1 Hz, 2H), 7.33 (br s,1H), 7.26 & 7.15 (2 singlets, amide rotamers, Ar—H, 1H), ˜4.9 (1Hpartially obscured by water peak), 4.68 (s, 2H), 4.06-3.88 (m, 3H),3.73-3.58 (m, 1H), 3.33-3.18 (m, 1H), 3.07-2.92 (m, 2H), 2.83-2.73 (m,2H), 2.44 & 2.34 (2 singlets, amide rotamers, Ar—CH₃, 3H), 2.25-1.91 (m,6H), 1.91-1.50 (m, 4H). ¹H NMR (400 MHz, CDCl₃): δ 7.64 (m, 2H), 7.34(m, 2H), 7.13-6.93 (m, 2H), 4.99 (m, 1H), 4.75 (s, 2H), 3.98 (m, 2H),3.73 (m, 1H), 3.53 (m, 1H), 3.31-2.83 (m, 5H), 2.41 (m, 1H), 2.37-1.61(m, 11H), 1.44 (m, 1H).

Compound 393.4-(1-(2-Ethyl-4-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but compound 211.2 was used in place of compound 2.2. m/z (ES+)455 (M+H)⁺.

Compound 394.4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 393but compound 152.1 was used in place of methyl 2-bromo-4-methylbenzoate.m/z (ES+) 455 (M+H)⁺.

Compound 395.4-(1-(4-Ethyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile.The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 394but compound 11.2HCl salt was used in place of compound 1.5. m/z (ES+)473 (M+H)⁺.

Compound 396.4-(1-(2,4-Diethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 except compounds 204.3 and 11.2 were used in place of compounds2.2 and 1.5 respectively. m/z (ES+) 487 (M+H)⁺.

Compound 397.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-diethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 except compound 204.3 was used in place of compound 2.2. m/z (ES+)510 (M+H)⁺.

Compound 398.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1,2, and 394. m/z (ES+) 496 (M+H)⁺.

Compound 399.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-ethyl-2-methylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1,2, and 394, but using compound 11.2HCl salt in place of compound 1.5.m/z (ES+) 514 (M+H)⁺.

Compound 400.1. 3-Methyldihydro-2H-pyran-4(3H)-one

A 1-L three neck round-bottom flask was purged and maintained with anitrogen atmosphere and a solution of LDA (2 M THF, 132 mL, 1.20 equiv)in tetrahydrofuran (300 mL). The mixture was cooled to −78° C., then asolution of dihydro-2H-pyran-4(3H)-one (22.0 g, 220 mmol, 1.00 equiv) inhexamethylphosphoramide (40 mL, 230 mmol, 1.05 equiv) was addeddrop-wise followed by drop-wise addition of methyliodide (34 mL, 550mmol, 2.5 equiv) at −78° C. The resulting solution was stirred at −78°C. for 5 min, then at 25° C. for 5 min. The reaction was carefullyquenched with saturated aqueous NH₄Cl (80 mL) and extracted with ether(2×100 mL). The combined organics was dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography with PE/Et₂O (5:1) as the eluent to obtain the titlecompound as a yellow oil (6.00 g, 24%).

Compound 400.2. 3-Bromo-5-methyldihydro-2H-pyran-4(3H)-one

A 250-mL three neck round-bottom flask was purged and maintained with anitrogen atmosphere. LDA (2.0 M in THF)(6 mL, 12 mmol, 1.20 equiv) andtetrahydrofuran (30 mL) were added. The solution was cooled to −78° C.and then TMSCl (7 mL, 55 mmol) was added drop-wise and stirred at −78°C. for 5 min. A solution of 3-methyldihydro-2H-pyran-4(3H)-one (compound400.1, 1.14 g, 9.99 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) wasadded drop-wise and the resulting mixture was stirred at −78° C. for 10min. The mixture was carefully quenched with a mixture of triethylamine(15 mL) and saturated aqueous NaHCO₃ (100 mL). The aqueous was extractedwith ether (2×50 mL), and the combined organics was washed with aqueouscitric acid (3×100 mL), dried (K₂CO₃), filtered and concentrated invacuo to obtain the intermediate enol silyl ether as a colorless oil.The enol silyl ether was dissolved in tetrahydrofuran (20 mL) and thesystem was purged with nitrogen. The mixture was cooled to 0° C., andthen N-bromosuccinimide (1.95 g, 11.0 mmol, 1.10 equiv) was addedportion-wise. The resulting mixture was stirred at 25° C. for 1 h, thenquenched with saturated aqueous NaHCO₃ (30 mL). The aqueous wasextracted with ether (2×30 mL), and the combined organics was dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography with PE/Et₂O (5:1) as the eluent to obtainthe title compound as a colorless oil (1.00 g, 52%).

Compound 400.3.2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid

Into around-bottom flask, was placed a solution of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2, 800 mg, 4.14mmol, 1.6 equiv) in N,N-dimethylformamide (5 mL). Ammonium hydroxide(25% NH₃ in H₂O) (530 mg, 7.8 mmol, 3.0 equiv), NH₄OAc (904 mg, 11.7mmol, 4.50 equiv) and 2-ethyl-5-formyl-4-methylbenzoic acid (compound211.4, 500 mg, 2.60 mmol, 1.00 equiv) were added to the flask. Theresulting mixture was stirred at 130° C. for 2 h, then concentrated invacuo. The residue was purified by silica gel chromatography withdichloromethane/methanol (70/1) as the eluent to obtain the titlecompound as a white solid (30.0 mg, 2%).

Compound 400.4-(1-(2-Ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, was placed a solution of2-ethyl-4-methyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid (compound 400.3, 30 mg, 0.10 mmol, 1.0 equiv) in DMF/DCM (5/5 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 50 mg, 0.22mmol, 2.2 equiv), EDC (40 mg, 2.0 equiv) and 4-dimethylaminopyridine (28mg, 2.0 equiv) were added. The resulting solution was stiffed overnightat 25° C., then quenched with water (10 mL). The mixture was extractedwith ethyl acetate (3×5 mL), and the combined organic layers was dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatraphy with ethyl acetate/petroleum ether (2:1) asthe eluent to obtain the title compound as a light yellow solid (3.2 mg,7%). m/z (ES+) 469 (M+H)⁺.

Compound 401.4-(1-(4-Cyclopropyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 392but compound 142.2 was used in place of compound 152.3. m/z (ES+) 467(M+H)⁺.

Compound 402.4-(1-(4-Cyclopropyl-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 392but compound 226.5 was used in place of compound 230.1. m/z (ES+) 481(M+H)⁺.

Compound 403. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but compound 142.2 and dimethyl dicarbonate/DIEA were used inplace of compound 2.2. and acetic anhydride respectively. m/z (ES+) 524(M+H)⁺.

Compound 404.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclopropyl-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compounds 1and 2 but using compound 142.2 was used in place of compound 2.2. m/z(ES+) 508 (M+H)⁺.

Compound 405.4-(1-(4-Cyclobutyl-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound392, except compound 11.2HCl salt was used in place of compound 1.5. m/z(ES+) 499 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.97 (m, 2H), 7.97 (m, 2H),7.67-7.53 (m, 2H), 4.80 (s, 2H), 4.10 (m, 2H), 3.75 (m, 1H), 3.55 (m,2H), 3.27 (m, 1H), 2.90 (m, 2H), 2.53 and 2.43 (2 singlets, amiderotamers, ArCH₃, 3H), 2.38-1.80 (m, 10H).

Compound 406.1.5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoicacid

To a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound392.1, 2.00 g, 9.16 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL)were added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (9.00 g,16.2 mmol, 2.00 equiv), ammonium hydroxide (3.84 g, 27.4 mmol, 3.00equiv, 25%), and NH₄OAc (3.18 g, 41.3 mmol, 4.50 equiv). The resultingmixture was stirred overnight at 130° C. under nitrogen. After coolingto ambient temperature, the mixture was diluted with 50 mL of ethylacetate, washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure. The residue waspurified using silica gel column chromatography withdichloromethane/methanol (20:1) as eluent to furnish 2.00 g (27%) of thetitle compound as a brown solid.

Compound 406.2. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

To a solution of5-(5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoicacid (compound 406.1, 1.00 g, 1.22 mmol, 1.00 equiv, 50%) inN,N-dimethylformamide (5 mL) were added 4-(piperidin-4-yl)benzonitrilehydrochloride salt (compound 1.5, 270 mg, 1.21 mmol, 1.00 equiv),EDC.HCl (460 mg, 2.40 mmol, 2.00 equiv), and 4-dimethylaminopyridine(296 mg, 2.42 mmol, 2.00 equiv). The resulting mixture was stiffed at25° C. overnight. The mixture was then diluted with 30 mL of ethylacetate, washed with 3×30 mL of brine, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to yield 890 mg (63%)of the title compound as a brown solid.

Compound 406.3.4-(1-(4-Cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

A solution of tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(406.2, 600 mg, 0.620 mmol, 1.00 equiv, 60%) in dichloromethane (3 mL)and trifluoroacetic acid (1.5 mL) was stirred for 3 h at 25° C., thendiluted with 5 mL of hydrochloric acid (3 mol/L) and 10 mL of water. Theresulting mixture was washed with 3×20 mL of ethyl acetate and the pHwas then adjusted to ˜9 with sodium hydroxide (aq, 3 M). The resultingmixture was extracted with 4×20 mL of dichloromethane. The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure to yield 140 mg (37%) of the title compound as a brown solid.

Compound 406.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution of4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(406.3, 190 mg, 0.30 mmol, 1.00 equiv, 75%) in tetrahydrofuran (10 mL)were added NaBH(OAc)₃ (252 mg, 1.13 mmol, 3.00 equiv, 95%) and HCHO(37%) (2.2 mL, 2.00 equiv). The resulting mixture was stiffed for 2 h at40° C. in an oil bath and then concentrated under reduced pressure. Theresidue was diluted with dichloromethane and washed with aqueoussaturated sodium bicarbonate and brine. The organic layer was dried(Na₂SO₄) and concentrated. The crude product (˜80 mg) was purified byPrep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)):Column, Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with0.03% NH₃H₂O and CH₃CN (36% CH₃CN up to 48% in 8 min, up to 100% in 1min, down to 36% in 1.5 min); Detector, Waters 2489 254&220 nm. Thefractions containing pure compound were combined and lyophilized toyield 23.4 mg (16%) of the title compound as a white solid. m/z (ES+)494 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ 7.69 (d, J=6.0 Hz, 2H), 7.48 (d,J=6.0 Hz, 2H), 7.37-7.31 (m, 1H), 7.26 & 7.15 (2 singlets, amiderotamers, Ar—H, 1H), ˜4.9 (1H partially obscured by water peak),4.02-3.90 (m, 1H), 3.73-3.57 (m, 1H), 3.57 (s, 2H), 3.34-3.21 (m, 1H),3.06-2.94 (m, 2H), 2.90-2.77 (m, 4H), 2.54 (s, 3H), 2.45 & 2.34 (2singlets, amide rotamers, ArCH₃, 3H), 2.11-1.86 (m, 6H), 1.86-1.54 (m,4H).

Compound 407.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 11.2HCl salt was used in place of compound 1.5. m/z(ES+) 512 (M+H)⁺.

Compound 408.4-(1-(4-Methyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 406except 3-iodo-4-methylbenzoic acid was used in place of compound 230.1.m/z (ES+) 440 (M+H)⁺.

Compound 409.4-(1-(4-Cyclobutyl-2-methyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

To a solution of4-(1-(4-cyclobutyl-2-methyl-5-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(406.3, 180 mg, 0.300 mmol, 1.00 equiv, 80%) in N,N-dimethylformamide (5mL) were added dimethyl dicarbonate (176 mg, 1.31 mmol, 5.00 equiv) andDIEA (169 mg, 1.31 mmol, 5.00 equiv). The resulting solution was stirredovernight at 25° C. and then quenched with 20 mL of methanol. Theresulting mixture was concentrated under reduced pressure and the crudeproduct was purified by Prep-HPLC using the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH3CN (28% CH3CN up to 43% in 8min, up to 100% in 3 min, down to 28% in 2 min); Detector, Waters 2489254&220 nm The fractions containing pure compound were combined andlyophilized to yield 29.9 mg (19%) of the title compound as a whitesolid. m/z (ES+) 538 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.70 (m, 2H),7.50-7.35 (m, 4H), 4.90 (m, 1H), 4.70 (s, 2H), 4.00 (m, 2H), 3.80 (m,4H), 3.60 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.85 (m, 2H), 2.50 and2.40 (2 singlets, amide rotamers, ArCH₃, 3H), 2.16-2.00 (m, 6H),1.86-1.64 (m, 4H).

Compound 410. Methyl2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutyl-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 11.2 was used in place of compound 1.5. m/z (ES+)556 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.78 (m, 2H), 7.67 (m, 2H),7.35-7.20 (m, 2H), 4.80 (m, 1H), 4.55 (s, 2H), 4.00 (m, 1H), 4.84 (m,2H), 3.77 (s, 3H), 3.60 (m, 1H), 3.28 (m, 1H), 2.80 (s, 2H), 2.47 and2.36 (2 singlets, amide rotamers. ArCH₃. 3M. 2.30-1.80 (m. 9M. 1.62 (m,1H), 1.32 (m, 1H).

Compound 411. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropyl-4-ethylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 226.5 was used in place of compound 230.1. m/z(ES+) 538 (M+H)⁺.

Compound 412.4-(1-(4-Cyclopropyl-2-ethyl-5-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 226.5 was used in place of compound 230.1. m/z(ES+) 494 (M+H)⁺.

Compound 413.1. 4-Cyclobutyl-3-iodobenzoic acid

A solution of compound 168.2 (11.0 g, 34.8 mmol, 1.00 equiv) and sodiumhydroxide (4.00 g, 100 mmol, 3.00 equiv) in methanol (˜100 mL) wasstirred at 50° C. overnight. After cooling to ambient temperature, themixture was concentrated to dryness. The residue was taken up in water(50 mL) equiv and washed with ethyl acetate. The pH of the aqueous layerwas adjusted to 3-4 with 6 M aqueous hydrogen chloride. The resultingprecipitate was collected by filtration and dried to yield 8.60 g (82%)of the title compound as a white solid.

Compound 413.4-(1-(4-Cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound392, except compound 413.1 was used as in place of compound 230.1. m/z(ES+) 477 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.76-7.65 (m, 5H), 7.48 (m,2H), 5.00 (m, 1H), 4.80 (s, 2H), 4.10 (m, 2H), 3.80 (m, 2H), 3.45 (m,1H), 3.04 (m, 2H), 2.90 (m, 2H), 2.18-1.95 (m, 6H), 1.85-1.77 (m, 4H).

Compound 414.4-(1-(4-Cyclobutyl-3-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound413, except compound 11.2HCl salt was used in place of compound 1.5. m/z(ES+) 485 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.82-7.77 (m, 3H), 7.68-7.65(m, 4H), 4.80 (m, 3H), 4. 90 (m, 2H), 3.83-3.46 (m, 3H), 2.90 (m, 2H),2.29 (m, 1H), 2.18-1.83 (m, 10H).

Compound 415.4-(1-(4-Cyclobutyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound414, except 3-methyldihydro-2H-pyran-4(3H)-one was used in place ofdihydro-2H-pyran-4(3H)-one. m/z (ES+) 499 (M+H)⁺.

Compound 416.4-(1-(4-Cyclopropyl-3-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound413, except bromo(cyclopropyl)magnesium and3-methyldihydro-2H-pyran-4(3H)-one were used in place ofbromo(cyclobutyl)magnesium and dihydro-2H-pyran-4(3H)-one respectively.m/z (ES+) 467 (M+H)⁺.

Compound 417.4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 413.1 was used in place of compound 230.1. m/z(ES+) 480 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.72-7.63 (m, 4H), 7.56 (s,1H), 7.49 (m, 2H), 4.82 (m, 1H), 4.56 (s, 2H), 3.89 (m, 2H), 3.80 (m,2H), 3.08 (m, 2H), 3.04 (s, 3H), 2.99 (m, 2H), 2.18-1.66 (m, 11H).

Compound 418.4-(1-(4-Cyclobutyl-3-(5-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound417, except compound 11.2HCl salt was used in place of compound 1.5. m/z(ES+) 498 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.79 (m, 2H), 7.74-7.59 (m,5H), 4.73 (br s, 1H), 4.54 (br s, 2H), 3.94 (m, 2H), 3.76 (br s, 2H),3.61 (br s, 1H), 3.20 (br s, 2H), 3.16 (s, 3H), 2.39-1.96 (m, 10H), 1.79(m, 1H).

Compound 419. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 413.1 was used in place of compound 230.1. m/z(ES+) 524 (M+H).

Compound 420. Methyl2-(5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compounds 413.1 and 11.2 were used in place of compounds230.1 and 1.5 respectively. m/z (ES+) 542 (M+H).

Compound 421. Ethyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 413.1 and diethyl dicarbonate were used in place ofcompound 230.1 and dimethyl dicarbonate respectively. m/z (ES+) 538(M+H).

Compound 422. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclopropylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound421, except bromo(cyclopropyl)magnesium and dimethyl diethyl dicarbonatewere used in place of bromo(cyclobutyl)magnesium and diethyl dicarbonaterespectively. m/z (ES+) 510 (M+H).

Compound 423.4-(1-(2,4-Dimethyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

A mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 62 mg), oxetan-3-one (18 μl), sodium cyanotrihydroborate(18 mg), and acetic acid (80 μl) in MeOH/THF (1:1 v/v) was stirred for16 hours. The reaction was then diluted with dichloromethane, washedwith saturated sodium bicarbonate solution followed by brine. Theorganic layer was dried (MgSO₄) and concentrated. The residue waspurified by preparative TLC at 8% MeOH in DCM to give 42 mg white solid(60%). m/z (ES+) 496 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d,2H), 7.32 (d, 2H), 7.27 and 7.20 (2 singlet, amide rotamers, 1H), 7.02(s, 1H), 4.96 (s, 1H), 4.74 (m, 4H), 3.88-3.77 (m, 1H), 3.63 (d, 1H),3.49 (d, 2H), 3.08 (t, 1H), 2.97-2.62 (m, 6H), 2.45 (d, 3H), 2.31 and2.22 (2 singlets, amide rotamers, 3H), 2.11-1.40 (m, 4H).

Compound 424.4-(1-(5-(5-Cyclopropyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 423.m/z (ES+) 480 (M+H)⁺. □¹H NMR (400 MHz, Chloroform-d) δ 10.58, 7.61 (d,2H), 7.33 (d, 2H), 7.23 and 7.15 (2 singlet, amide rotamers, 1H), 6.97(s, 1H), 4.93 (s, 1H), 3.80-3.66 (m, 2H), 3.64-3.49 (m, 1H), 3.02 (m,3H), 2.91-2.64 (m, 4H), 2.41 (d, 3H), 2.28 and 2.18 (2 singles, amiderotamers, 3H), 2.07-1.86 (m, 2H), 1.84-1.37 (m, 2H), 0.66-0.40 (m, 4H).

Compound 425.4-(1-(2,4-Dimethyl-5-(5-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 406 butusing compound 2.9 in place of compound 406.3. m/z (ES+) 454 (M+H)⁺.

Compound 426.4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 423.m/z (ES+) 468 (M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.63 (d, 2H),7.40-7.19 (m, 3H), 7.04 (s, 1H), 4.95 (s, 1H), 3.75-3.51 (m, 3H), 3.09(m, 1H), 2.95-2.77 (m, 6H), 2.71 (m, 2H), 2.46 (s, 3H), 2.30 and 2.21 (2singlets, amide rotamers, 3H), 2.12-1.89 (m, 1H), 1.85-1.43 (m, 3H),1.22 (m, 3H).

Compound 427.4-(1-(5-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

A mixture of4-(1-(2,4-dimethyl-5-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile(compound 2.9, 88 mg), 1-bromo-2-fluoroethane (150 μl), potassium iodide(50 mg), and triethyl amine (140 μl) in DMF (2 ml) was stirred for 48hours. The reaction mixture was then diluted with dichloromethane andwashed with brine. The organic layer was dried (MgSO₄) and concentrated.The residue was purified by prep. TLC using 8% MeOH in DCM to give 51 mgof a white solid (52%). m/z (ES+) 486 (M+H)⁺. ¹H NMR (400 MHz,Chloroform-d) 7.63 (d, 2H), 7.32 (d, 2H), 7.28 and 7.20 (2 singlets,amide rotamers, 1H), 7.00 (s, 1H), 4.93 (m, 1H), 4.67 (dt, J₁=47.6 Hz,J₂=4.9 Hz, 2H), 3.71 (d, 2H), 3.62 (d, 1H), 3.03-2.71 (m, 8H), 2.43 (d,3H), 2.29 and 2.19 (2 singlets, amide rotamers, 3H), 2.08-1.89 (m, 2H),1.85-1.49 (m, 2H), 3.18-3.05 (m, 1H).

Compound 428.4-(4-Fluoro-1-(5-(5-(2-fluoroethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 427 butusing compound 11.2HCl salt instead of compound 1.5. m/z (ES+) 504(M+H)⁺. ¹H NMR (400 MHz, Chloroform-d) δ 7.70 (d, 2H), 7.50 (d, 2H),7.28 and 7.21 (2 singlet, amide rotamers, 1H), 7.00 (s, 1H), 4.92-4.77(m, 1H), 4.66 (dt, J₁=47.7 Hz, J₂=4.8 Hz, 2H), 3.68 (d, 2H), 3.58-3.35(m, 2H), 3.33-3.11 (m, 1H), 2.95 (dt, 4H), 2.76 (d, 2H), 2.42 (s, 3H),2.28 and 2.20 (2 singlets, amide rotamers, 3H), 2.16-1.72 (m, 4H).

Compound 429.1. 1-tert-Butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100mmol, 1.00 equiv) in ether (60 mL)-30° C. was added dropwise a solutionof BF₃.Et₂O (16.0 mL, 1.30 equiv) in ether (20 mL). After stirring 30min at −30° C., a solution of ethyl 2-diazoacetate (16.0 g, 140 mmol,1.30 equiv) in ether (20 mL) was added dropwise to the reaction at −30°C. The resulting solution was stirred for 1 h at −30° C., then warmed to25° C. and stirred for 2 h. The reaction was then quenched with 100 mLof 30% aqueous potassium carbonate. The resulting mixture was extractedwith 2×250 mL of ethyl acetate, and the combined organic layers werewashed with 2×50 mL of brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography with ethyl acetate/petroleum ether (1/10) as eluentto furnish 19.0 g (66%) of the title compound as a light yellow oil.

Compound 429.2. tert-Butyl 4-oxoazepane-1-carboxylate

To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate(429.1, 19.0 g, 66.6 mmol, 1.00 equiv) in 1,4-dioxane (190 mL) was addeddropwise sodium hydroxide (4.00 g, 100 mmol, 1.50 equiv) in water (100mL). The resulting mixture was stiffed at room temperature overnight.The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3 M) and theresulting solution was extracted with 2×50 mL of ethyl acetate. Thecombined organic layers were washed with 2×10 mL of brine, dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Thecrude residue was purified by silica gel chromatography using ethylacetate/petroleum ether (1:3) as eluent to furnish 11.0 g (77%) of thetitle compound as a yellow oil.

Compound 429.3. tert-Butyl 4-bromo-5-oxoazepane-1-carboxylate

To a solution tert-butyl 4-oxoazepane-1-carboxylate (429.2, 11.0 g, 51.6mmol, 1.00 equiv) in chloroform (220 mL) 0° C. was added dropwisesolution of Br₂ (12.4 g, 77.6 mmol, 1.50 equiv) in chloroform (110 mL).The resulting mixture was stirred at room temperature overnight. Theformed solids were collected by filtration and taken up in 200 mL ofdichloromethane. Et₃N (12.2 g) and (Boc)₂O (8.70 g, 40.3 mmol, 1.00equiv) were added to the mixture at 0° C. The resulting solution wasstirred for 3 h at room temperature, and then concentrated underpressure. The crude residue was purified by silica gel chromatographyusing ethyl acetate/petroleum ether (1:10) as eluent to give 4.00 g(27%) of the title compound as a yellow oil.

Compound 429.4. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate

To a solution of tert-butyl 4-bromo-5-oxoazepane-1-carboxylate (429.3,844 mg, 2.89 mmol, 2.00 equiv) in N,N-dimethylformamide (5 mL) wereadded compound 16.4 (500 mg, 1.44 mmol, 1.00 equiv), NH₄OH (606 mg, 4.33mmol, 3.00 equiv, 25%), and NH₄OAc (500 mg, 6.49 mmol, 4.50 equiv). Theresulting mixture was stirred overnight at 130° C. under nitrogen. Aftercooling to ambient temperature, 30 mL of ethyl acetate was added. Theresulting mixture was washed with 3×20 mL of brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography with ethyl acetate as eluent toyield 343 mg (43%) of the title compound as a brown solid.

Compound 429.5.4-(1-(5-(1,4,5,6,7,8-Hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitriletrifluoroacetate

To a solution of compound 429.4 (550 mg, 0.990 mmol, 1.00 equiv) in DCM(3 mL) was added trifluoroacetic acid (1.3 mL). After stirring at 25° C.for 4 h, the mixture was concentrated under reduced pressure and driedto yield 400 mg (71%) of the title compound as a brown solid.

Compound 429.4-(1-(5-(6-Acetyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except compound 429.5 was used in place of compound 2.9. m/z (ES+) 496(M+H)⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.65 (d, J=8.1 Hz, 2H), 7.44-7.32 (m,4H), 4.90 (m, 1H), 3.86 (m, 2H), 3.60 (m, 1H), 3.20 (m, 2H), 3.00 (m,6H), 2.40-2.31 (m, 6H), 2.20 (s, 3H), 2.00-1.60 (m, 5H).

Compound 430. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4,5,7,8-tetrahydroimidazo[4,5-d]azepine-6(1H)-carboxylate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound409, except compound 429.5 was used in place of compound 406.3. m/z(ES+) 496 (M+H)⁺.

Compound 431.4-(1-(5-(6-Isopropyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of4-(1-(5-(1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitriletrifluoroacetate (429.5, 80.0 mg, 0.140 mmol, 1.00 equiv) inN,N-dimethylformamide (5 mL) were added 2-iodopropane (270 mg, 1.59mmol, 9.00 equiv) and DIEA (205 mg, 1.59 mmol, 9.00 equiv). Theresulting solution was stirred overnight at 80° C. in an oil bath. Aftercooling to ambient temperature, the mixture was diluted with 50 mL ofethyl acetate, washed with 3×20 mL of brine, dried (Na₂SO₄), andconcentrated. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:10) as eluent. Theproduct (50 mg) was further purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um,19*150 mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN (38.0% CH₃CNup to 51.0% in 8 min, up to 100.0% in 2 min, down to 38.0% in 1 min);Detector, Waters 2489 254&220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 15.0 mg (21%) of the titlecompound as a white solid. m/z (ES+) 496 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ 7.69 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.33-7.23 (m, 2H), 4.86 (m, 1H),3.65 (m, 1H), 3.30 (m, 1H), 3.15 (m, 1H), 2.99 (m, 6H), 2.80 (m, 4H),2.45 (s, 3H), 2.40 and 2.29 (2 singlets, amide rotamers, 3H), 2.10 (m,1H), 1.70 (m, 3H), 1.15 (d, J=6.8 Hz, 6H).

Compound 432.4-(1-(5-(5-Ethyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 431except compound 2.9 was used in place of compound 429.5. m/z (ES+) 482(M+H)⁺.

Compound 433.4-(1-(4-Cyclopropyl-5-(5-isopropyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound431, except compound 142.2 and tert-butyl3-bromo-4-oxopiperidine-1-carboxylate were used in place of compound152.3 and tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (429.2)respectively. m/z (ES+) 508 (M+H)⁺.

Compounds 434 and 435.4-(1-(2,4-Dimethyl-5-(4,5,7,8-tetrahydro-1H-oxepino[4,5-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrileand4-(1-(2,4-dimethyl-5-(4,6,7,8-tetrahydro-1H-oxepino[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compounds were prepared as a separable mixture using standardchemical manipulations and procedures similar to those used for thepreparation of compound 429, except oxepan-4-one was used in place ofcompound tert-butyl 4-oxoazepane-1-carboxylate (429.2). 434: m/z (ES+)455 (M+H)⁺. 435: m/z (ES+) 455 (M+H)⁺.

Compound 436.4-(1-(5-(6-(2-Fluoroethyl)-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound427, except compound 429.5 was used in place of compound 2.9. m/z (ES+)500 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.64 (d, J=8.1 Hz, 2H), 7.43 (m,2H), 7.28-7.20 (m, 2H), 4.86 (m, 1H), 4.60 (dt, J₁=47.7 Hz, J₂=4.8 Hz,2H), 3.60 (m, 1H), 3.20 (m, 1H), 3.00 (m, 8H), 2.80 (m, 4H), 2.40 (s,3H), 2.35 and 2.24 (2 singlets, amide rotamers, 3H), 1.99 (m, 1H), 1.70(m, 3H).

Compound 437.4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound418, except compound 429.3 was used in place of compound tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 512 (M+H)⁺.

Compound 438.4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound407, except compound 429.3 was used in place of compound tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 526 (M+H)⁺.

Compound 439.4-(1-(4-Cyclobutyl-3-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound417, except compound 429.3 was used in place of compound tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 494 (M+H)⁺.

Compound 440.4-(1-(4-Cyclobutyl-2-methyl-5-(6-methyl-1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepin-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound406, except compound 429.3 was used in place of compound tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 508 (M+H)⁺.

Compound 441.(R)-1-(2-Chloro-5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-4-ethylphenyl)-3-((tetrahydrofuran-2-yl)methyl)urea

The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 67 andusing compound 178.2 in place of compound 48.1. m/z (ES+) 513 (M+H)⁺.

Compound 442.(R)-1-(2-Chloro-4-ethyl-5-(4-fluoro-4-(4-fluorophenyl)piperidine-1-carbonyl)phenyl)-3-((tetrahydrofuran-2-yl)methyl)urea

The title compound was prepared using readily available reagents andprocedures similar to those used for the preparation of compound 67 andusing compound 178.2 in place of compound 48.1. m/z (ES+) 506 (M+H)⁺.

Compound 443.1. Methyl 4-cyclobutyl-3-nitrobenzoate

To a solution of methyl 4-cyclobutylbenzoate (compound 168.1, 3.80 g,20.0 mmol, 1.00 equiv) in acetic anhydride (12 mL) 0° C. was addeddropwise fuming HNO₃ (5 mL, 97%). The resulting mixture was stirred at30° C. in an oil bath. After 2 h, 30 mL of water was carefully added andthe mixture was extracted with 2×30 mL of ethyl acetate. The combinedorganic layers were washed with aqueous saturated NaHCO₃ (note: gasevolution), dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:25) as eluent tofurnish 3.00 g (64%) of the title compound as a light yellow oil.

Compound 443.2. Methyl 3-amino-4-cyclobutylbenzoate

A flask containing a solution of methyl 4-cyclobutyl-3-nitrobenzoate(compound 443.1, 2.50 g, 10.6 mmol, 1.00 equiv) in methanol (30 mL) waspurged with nitrogen. Palladium on carbon (10%, 60% water, 1.2 g) wasadded and the flask was carefully purged further with nitrogen. Theatmosphere was then changed to hydrogen and the mixture was stirredovernight at 20° C. After purging the system with nitrogen, the solidswere then removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:5) as eluent toyield 1.60 g (73%) of the title compound as a white solid.

Compound 443.3. 3-Amino-4-cyclobutylbenzoic acid

Into around-bottom flask, was placed a solution of methyl3-amino-4-cyclobutylbenzoate (1.00 g, 4.87 mmol, 1.00 equiv) and sodiumhydroxide (compound 443.2, 800 mg, 20.0 mmol, 4.00 equiv) in a solventmixture of methanol and H₂O (20/10 mL). The resulting solution wasstirred for 8 h at 20° C. After cooling to ambient temperature, theorganic solvent was removed under reduced pressure. The pH of theremaining aqueous layer was adjusted to ˜4-5 with HCl (aqueous, 1 M).The resulting precipitate was then collected by filtration and dried tofurnish 500 mg (54%) of the title compound as a white solid.

Compound 443.4.4-(1-(3-Amino-4-cyclobutylbenzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using a procedure similar to that usedfor the preparation of compound 42.2, but using compound 443.3 in placeof compound 42.1.

Compound 443.(R)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 64,using compound 443.4 and (R)-tetrahydrofuran-3-amine in place ofcompound 42.2 and (R)-(tetrahydrofuran-2-yl)methanamine respectively.m/z (ES+) 491 (M+H)⁺.

Compound 444.(S)-1-(5-(4-(4-Cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclobutylphenyl)-3-(tetrahydrofuran-3-yl)urea

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound443, using (S)-tetrahydrofuran-3-amine in place of(R)-tetrahydrofuran-3-amine. m/z (ES+) 491 (M+H)⁺. ¹H NMR (300 MHz,CD₃OD): δ 7.83-7.77 (m, 3H), 7.69 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.1 Hz,1H), 7.22 (dd, J=7.8 Hz, J=1.5 Hz, 1H), 4.80-4.62 (m, 1H), 4.39-4.31 (m,1H), 4.02-3.78 (m, 4H), 3.72-3.49 (m, 3H), ˜3.3 (1H partially obscuredby methanol solvent peak), 2.50-2.37 (m, 2H), 2.37-1.78 (m, 10H).

Compound 445.1. Methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate.

To a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (compound238.1, 500 mg, 2.03 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0°C. was added dropwise a solution of LiHMDS (680 mg, 4.06 mmol, 2.00equiv) in tetrahydrofuran (5 mL). After 30 min of stirring at 0° C., asolution of propanoyl chloride (280 mg, 3.03 mmol, 1.50 equiv) intetrahydrofuran (5 mL) was added dropwise. The resulting mixture wasstirred for 3 h at 15° C., and then concentrated under reduced pressure.The residue was diluted with 40 mL of ethyl acetate, washed with ofbrine (3×40 mL), dried (Na₂SO₄), and concentrated under reducedpressure. This resulted in 500 mg (crude) of the title compound as abrown oil.

Compound 445.2. Methyl4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate

To a solution of methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate(compound 445.1, 300 mg, 0.990 mmol, 1.00 equiv) in methanol (15 mL) wasadded NH₂NH₂.H₂O. The resulting solution was stiffed for 1.5 h at 80° C.in an oil bath, and then concentrated under reduced pressure. Theresidue was diluted with 100 mL of ethyl acetate, then washed with 3×100mL of brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified using silica gel columnchromatography with ethyl acetate/petroleum ether (1:5) as eluent toyield 188 mg (64%) of the title compound as a yellow oil.

Compound 445.3. 4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoicacid

To a solution of methyl4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate (compound445.2, 188 mg, 0.630 mmol, 1.00 equiv) in methanol (6 mL) was addedaqueous sodium hydroxide (76.0 mg, 1.90 mmol, 3.00 equiv in 3 mL water).The resulting solution was stirred for 2 h at 70° C. in an oil bath.After cooling to ambient temperature, the mixtue was concentrated underreduced pressure. The residue was diluted with 20 mL of H₂O. The pH ofthe mixture was adjusted to −4 with aqueous HCl (2 M). The mixture wasthen extracted with 3×20 mL of ethyl acetate. The combined organiclayers were washed with 3×20 mL of brine, dried (Na₂SO₄), andconcentrated under reduced pressure. This resulted in 0.180 g (crude) ofthe title compound as a yellow oil.

Compound 445.4-(1-(4-Cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile

To a solution of4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoic acid (compound445.3, 130 mg, 0.460 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL)were added 4-(Piperidin-4-yl)benzonitrile hydrochloride (1.5, 102 mg,0.460 mmol, 1.00 equiv), EDCI (176 mg, 0.920 mmol, 2.00 equiv), and4-dimethylaminopyridine (112 mg, 0.920 mmol, 2.00 equiv). The resultingsolution was stirred for 2 h at 30° C., and then diluted with 40 mL ofethyl acetate. The mixture was washed with 3×40 mL of brine, dried(Na₂SO₄), and concentrated under reduced pressure. The crude product waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (59.0% CH₃CN up to 73.0% in6 min, up to 100.0% in 7 min, down to 59.0% in 1 min); Detector, Waters2489 254&220 nm. The fractions containing pure compound were combinedand lyophilized to yield 150 mg (72%) of the title compound as a whitesolid. m/z (ES+) 453 (M+H)⁺.

Compound 446.1 Methyl4-cyclobutyl-2-methyl-5-((trimethylsilyl)ethynyl)benzoate

A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound152.3, 1.32 g, 4 mmol), trimethylsilylacetylene (663 μl, 4.8 mmol),Pd(PPh₃)₂Cl₂ (85 mg, 0.12 mmol) and copper iodide (CuI, 46 mg, 0.24mmol) in THF (8 ml) and triethylamine (2 ml) was degassed and thenheated to 80° C. for 1.5 hours under nitrogen. After cooling to ambienttemperature, the reaction was filtered through celite and concentrated.The residue was dissolved in ethyl acetate (EtOAc), washed with brine,dried over MgSO₄ and concentrated. The residue was purified by flashchromatography (SiO₂; 3% EtOAc in Hexane) to give 1.17 g (97%) of thetitle compound as a liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.15(s, 1H), 4.01-3.75 (m, 4H), 2.63 (s, 3H), 2.54-2.31 (m, 2H), 2.27-2.12(m, 2H), 2.12-1.98 (m, 1H), 1.94-1.80 (m, 1H), 0.28 (s, 9H).

Compound 446.2. Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate

To a solution of compound 446.1 (1.17 g, 3.9 mmol) in THF (6 ml) at −20°C. was added 4.1 ml TBAF (1.0 M in THF). The mixture was stirred for 30minutes at this temperature and was then diluted with water (15 ml) andextracted with EtOAc twice. The combined organic phases were washed withbrine, dried (MgSO₄), and concentrated. The residue was purified byflash chromatography (SiO₂; 2% EtOAc in Hexane) to give 816 mg (91%) ofthe title compound as a liquid. m/z (ES−) 227 (M−H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.05 (s, 1H), 7.20 (s, 1H), 4.02-3.80 (m, 4H), 3.25 (s, 1H),2.64 (s, 3H), 2.52-2.38 (m, 2H), 2.29-2.13 (m, 2H), 2.12-1.98 (m, 1H),1.93-1.79 (m, 1H).

Compound 446.3. Methyl4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate.

Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound 446.2, 180 mg,0.69 mmol) was dissolved in TMSN₃ (1 ml) in sealed tube. The reactionwas heated to 170° C. for 24 hours behind a blast shield then cooleddown to 0° C. EtOAc (10 ml) and water (20 ml) were added. The resultingmixture was stirred at RT for 1 hr. The organic phase was then washedwith brine, dried (MgSO₄), and concentrated. The residue was purified byflash chromatography (SiO₂; 0-30% EtOAc in Hexane) to give 92 mg (49%)of the title compound as a liquid. m/z (ES+) (272) (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 8.04 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 3.90 (s, 4H),2.69 (s, 3H), 2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H),1.86-1.76 (m, 1H).

Compound 446.4. 4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoicacid

A solution of methyl4-cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoate (compound 446.3,92 mg, 0.34 M) in 2N NaOH (1.5 ml) and methanol (MeOH) (4 ml) was heatedat 50° C. for 16 hours. After cooling to room temperature, the methanolwas removed under reduced pressure. The residue was neutralized with 2NHCl to pH 3-4 and extracted with EtOAc. The organic phase was thenwashed with brine, dried (MgSO₄), and concentrated to yield 83 mg of awhite solid that was used without further purification. m/z (ES−) 256(M−H)⁺.

Compound 446.4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl)piperidin-4-yl)benzonitrile

A mixture of the above acid (compound 446.4, 44 mg, 0.17 mmol), compound1.5 (42 mg, 0.19 M), EDCI (49 mg, 0.26 mmol), HOBt (33 mg, 0.19 mmol)and DIEA (120 □l, 0.68 mmol) in DMF (1 ml) was stirred at roomtemperature for 2.5 hours. The reaction was then diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, and concentrated. The residue was purified by flashchromatography (SiO₂; 8% Methanol in dichloromethane) and to yield 46 mgfoam of the title compound (70%). m/z (ES+) 426 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 12.20 (s, 1H), 7.70 (d, 1H), 7.66-7.49 (m, 2H), 7.44-7.21 (m,4H), 5.01 (d, 1H), 3.83 (p, 1H), 3.72 (d, 1H), 3.27-3.06 (m, 1H), 2.91(m, 2H), 2.46 (2 singlets, amide rotamers, 3H), 2.27-1.89 (m, 3H),1.86-1.43 (m, 7H).

Compound 447.4-(1-(4-Cyclobutyl-2-methyl-5-(2H-1,2,3-triazol-4-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using procedures similar to those usedfor preparation of compound 446 and using compound 11.2 HCl salt inplace of compound 1.5. m/z (ES+) (444) (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ12.00(s, 1H), 7.77 (s, 1H), 7.67 (m, 2H), 7.49 (d, 2H), 7.37 (m, 2H),4.92 (d, 1H), 3.85 (t, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H),2.45 (2 singlets, amide rotamers, 3H), 2.28-1.89 (m, 8H), 1.85 (m, 2H).

Compound 448.1. Methyl5-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoate

To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound130.1, 500 mg, 2.24 mmol, 1.00 equiv) in ethanol (5 mL) was added sodiumbicarbonate (396 mg, 4.71 mmol, 1.00 equiv) and3-bromodihydro-2H-pyran-4(3H)-one (compound 1.10.1, 186 mg, 1.04 mmol,1.00 equiv). The resulting solution was stiffed overnight at 80° C.under nitrogen. After cooling to room temperature the mixture wasconcentrated under reduced pressure. The residue was taken up 10 mL ofwater and ethyl acetate. The aqueous phase was extracted with 2×20 mL ofethyl acetate and the combined organic layers were dried (MgSO₄), andconcentrated under reduced pressure to yield 400 mg (56%) of the titlecompound as a yellow solid.

Compound 448.2.5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoic acid

A solution of compound 448.1 (304 mg, 1.00 mmol) and sodium hydroxide(aqueous, 280 mg, 7.00 mmol in 3 mL water) in methanol (5 mL) wasstirred for 1 h at 56° C. in an oil bath. After cooling to ambienttemperature, the methanol was removed under reduced pressure. The pH ofthe remaining aqueous layer was adjusted to 3˜4 with hydrogen chloride(aq., 2 M). The resulting precipitate was collected by filtration anddried in an oven under reduced pressure to yield 230 mg (79%) of thetitle compound as a yellow solid.

Compound 448.4-(1-(5-(6,7-Dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

A solution of compound 448.2 (100 mg, 0.35 mmol, 1.00 equiv) inN,N-dimethylformamide (3 mL), DIEA (140 mg, 1.08 mmol, 3.00 equiv), andHBTU (197 mg, 0.52 mmol, 1.50 equiv) was stirred for 0.5 h at 25° C. Asolution of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5,92.2 mg, 0.41 mmol, 1.10 equiv) in DIEA (1 mL) was added dropwise. Theresulting solution was stirred for 0.5 h at 25° C., then quenched with10 mL of water. The aqueous phase was extracted with 2×20 mL of ethylacetate and the combined organic layers were washed with 1×20 mL ofwater, 1×20 mL of brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified usingsilica gel column chromatography with ethyl acetate/petroleum ether(1:1) as eluent. The product was further purified by Prep-HPLC using thefollowing conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire PrepC18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH₃CN (25%CH₃CN up to 80% in 7 min, up to 100% in 1 min, down to 25% in 1 min);Detector, Waters 2489 254&220 nm. The fractions containing pure compoundwere combined and lyophilized to yield 134.9 mg (85%) of the titlecompound as a white solid. m/z (ES+) 458 (M+H)⁺.

Compound 449.1 and Compound 400.1.3,3-Dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) and3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1)

To a solution of LDA (2.0 M in heptanes/THF/ethylbenzene) (28 mL, 55mmol) was added dihydro-2H-pyran-4(3H)-one (4.612 g, 46 mmol) in THF (50mL) drop-wise under argon at −78° C. The mixture was stirred at −78° C.for 5 minutes, then iodomethane (14 mL, 225 mmol) in THF (500 ml) wasadded. The resulting mixture was allowed to warm to 0° C. and stirredfor 2 hours at 0° C. The reaction was allowed to warm to roomtemperature for 5 min, then cooled back to 0° C. and quenched withsaturated ammonium chloride (30 mL) and the mixture was extracted withether (2×50 mL). The combined organics was washed with brine (50 mL),dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (15% ethyl acetate in hexanes) toyield 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1) as an oil(694 mg, 13%) and 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) asan oil (860 mg, 16%).

Compound 449.2. 5-Bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one

A solution of lithium diisopropylamine (2.0 M inheptanes/THF/ethylbenzene) (2.5 ml, 5.1 mmol) diluted with THF (10 mL)under argon was cooled to −78° C. Chlorotrimethylsilane (2.5 mL, 19.5mmol) was added followed by 3,3-dimethyldihydro-2H-pyran-4(3H)-one(compound 449.1, 500 mg, 3.9 mmol) in THF (5 mL) and triethylamine (8.0mL, 57 mmol). The resulting mixture was stirred at −78° C. for 5 minutesand then quenched with saturated NaHCO₃ (20 mL). The mixture wasextracted with ether (30 mL) and the organics was washed with 1M citricacid (50 mL), dried (K₂CO₃), filtered and concentrated in vacuo. Theresidue was dissolved in THF (5 mL) and cooled to 0° C.N-Bromosuccinimide (694 mg, 3.9 mmol) was added and the resultingmixture was stirred at room temperature for 2 hrs and then quenched withsaturated NaHCO₃ (10 mL). The mixture was extracted with ether (2×20 mL)and the organics was washed with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (8% ethyl acetate in hexane) to yield the title compoundas an oil (150 mg, 18%).

Compound 449.3. Methyl5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate

A mixture of 5-bromo-3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound449.2, 150 mg, 0.72 mmol), methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 135 mg, 0.55 mmol), and potassium carbonate(228 mg, 1.65 mmol) in acetonitrile (8 mL) was heated at 100° C. for 48hrs. The mixture was concentrated in vacuo and the residue was dissolvedin ethyl acetate (10 mL) and washed with brine (20 mL), dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (50% ethyl acetate in hexanes) to yield the titlecompound as a white solid (27 mg, 15%).

Compound 449.4.5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoicacid

To methyl5-(7,7-dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 449.3, 27 mg, 0.086 mmol) in THF (3 mL) was added 2 M lithiumhydroxide (430 μl, 0.86 mmol) and the mixture was heated at 50° C. for16 hrs. The volatile solvents were removed in vacuo and the resultingresidue was neutralized with 2M HCl to pH=3 and concentrated in vacuo togive a white solid and used in the next reaction without doing furtherpurification. m/z (ES−) 299 (M−H)⁻.

Compound 449.4-(1-(5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

Crude5-(7,7-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoicacid (compound 449.4, 0.086 mmol) was dissolved in DMF (1 mL).4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 19 mg, 0.086mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(V) (HBTU) (65 mg, 0.17 mmol) and DIEA (45 μl, 0.26mmol) were added and the mixture was stiffed at room temperature for 16hrs. The mixture was then diluted with ethyl acetate (10 mL) and washedwith brine (10 mL), dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (ethyl acetate) toobtain the title compound as a solid foam (15 mg, 30%). m/z (ES+) 469(M+H)⁺.

Compound 450.4-(1-(2,4-Dimethyl-5-(7-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for preparation of compound 449,except 3-methyldihydro-2H-pyran-4(3H)-one (compound 400.1) was used inplace of 3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z(ES+) 455 (M+H)⁺.

Compound 451.1 and compound 451.2. tert-Butyl3-methyl-4-oxopiperidine-1-carboxylate and tert-butyl3,3-dimethyl-4-oxopiperidine-1-carboxylate

Sodium hydride (60% in mineral oil) (1.27 g, 31.8 mmol.), was suspendedin THF (80 mL) under an atmosphere of nitrogen. tert-Butyl4-oxopiperidine-1-carboxylate (6.0 g, 30 mmol) was added portion-wise atroom temperature. The mixture was stirred at room temperature for 1.5hours and then methyl iodide (3.8 mL, 6.1 mmol) was added. The mixturewas stirred at room temperature overnight and then cooled to 0° C. andcarefully quenched with water (20 mL). The mixture was extracted withethyl acetate (100 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified by silica gel chromatography (10:1hexane/ethyl acetate) to obtain compound 451.1 as a clear oil (1.7 g,27%) and compound 451.2 as a crystalline solid (963 mg, 14%).

Compound 451.3. tert-Butyl5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate

tert-Butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (0.963 g, 4.24mmol) as dissolved in THF (10 mL) and then phenyltrimethylammoniumtribromide (PTAT) (1.59 g, 4.24 mmol) was added. The mixture was stiffedat room temperature for 2 hours then water (20 mL) was added and mixturewas extracted with ethyl acetate (100 mL). The organics was dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by silica gel chromatography (10:1 hexane/ethyl acetate) toobtain compound 451.3 as a white crystalline solid (0.94 g, 73%).

Compound 451.4-(4-(5-(5-Acetyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)cyclohexyl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except tert-butyl 5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate(compound 451.3) was used in place of tert-butyl3-bromo-4-oxopiperidine-1-carboxylate. m/z (ES+) 510 (M+H)⁺.

Compound 452.4-(1-(5-(5-Isopropyl-7,7-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

4-(1-(5-(7,7-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(0.12 g, 0.26 mmol) (intermediate prepared in the synthesis of compound451), DMF (4 mL), acetic acid (69 μL, 1.21 mmol), sodiumtriacetoxyborohydide (0.11 g, 0.52 mmol) and acetone (0.50 mL, 6.8 mmol)were mixed and stirred at room temperature for 2 hours. The reaction wascarefully quenched with water (10 mL) and the mixture was extracted withethyl acetate (60 mL) and the organics was dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by preparative TLC(DCM/10% MeOH) followed by a second preparative TLC (ethyl acetate/5%MeOH) to obtain the title compound as a white powder (4.1 mg, 8.1%). m/z(ES+) 510 (M+H)⁺.

Compound 454.1. Phenyl 4-methoxy-2-methylpyridine-1(2H)-carboxylate

A 3-L four neck round-bottom flask was purged and maintained with anitrogen atmosphere and a solution of 4-methoxypyridine (30.0 g, 275mmol, 1.00 equiv) in tetrahydrofuran (1.2 L) was added. The mixture wascooled to −40° C. and phenyl chloroformate (45.0 g, 287 mmol, 1.05equiv) was added dropwise. The resulting solution was stirred for 1 h at−40° C., then methylmagnesium bromide (3M, 110 mL, 1.20 equiv) was addedto the reaction mixture while maintaining the temperature at −40° C. Theresulting solution was warmed slowly to 5-10° C. and stirred for 2 h,then carefully quenched with ice water (100 mL). The resulting mixturewas extracted with ethyl acetate (2×1 L) and the combined organics waswashed with brine (1×300 mL), dried (Na₂SO₄), filtered and concentratedin vacuo to yield the title compound as a light brown oil (71.0 g,>theoretical).

Compound 454.2. tert-Butyl2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

A 3-L four neck round-bottom flask was purged and maintained with anitrogen atmosphere and a solution of phenyl4-methoxy-2-methylpyridine-1(2H)-carboxylate (454.1, 70.0 g, 285 mmol,1.00 equiv) in tetrahydrofuran (1.2 L) was added. The solution wascooled to −78° C. then potassium tert-butoxide (128 g, 1.14 mol, 4.00equiv) was added portion-wise. The resulting mixture was stirred at10-15° C. for 20 h then concentrated in vacuo. The residue was dissolvedin EtOAc (1.5 L), then carefully quenched with ice water (200 mL). Thelayers were separated and the aqueous was extracted with additionalethyl acetate (100 mL). The combined organics was washed with aqueoussodium hydroxide (1.5 M, 3×100 mL), aqueous hydrochloric acid (1 M,2×100 mL), and brine (200 mL), dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by silica gel chromatography (ethylacetate/petroleum ether, 1:200-1:20) as the eluent to obtain the titlecompound as a light yellow oil (31.0 g, 51%).

Compound 453.1 and compound 454.3. tert-Butyl6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(453.1) and tert-butyl2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(454.3)

A 500-mL three neck round-bottom flask was purged and maintained with anitrogen atmosphere and a solution of tert-butyl2-methyl-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (compound 454.2,10.5 g, 49.5 mmol, 1.00 equiv) in tetrahydrofuran (300 mL) was added.The solution was cooled to −78° C. and L-Selectride (1 M in THF, 60 mL,1.20 equiv) was added drop-wise. The resulting solution was stirred for2 h at −78° C. then chlorotrimethylsilane (6.96 g, 64.1 mmol, 1.30equiv) was added drop-wise with stiffing. The resulting solution wasstirred for 16 h at 10-15° C., and then concentrated in vacuo. Theresidue was diluted with n-hexane (500 mL) and the solids were filteredaway. The filtrate was concentrated in vacuo and the residue purified bysilica gel chromatography ethyl acetate/petroleum ether (1:100-1:20) asthe eluent to obtain a mixture of the title compounds as a light yellowsolid (10.0 g, 71%).

Compound 453.2 and compound 454.4. tert-Butyl5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (453.2) and tert-butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (454.4)

Into a round-bottom flask, was placed a solution of a mixture oftert-butyl6-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylateand tert-butyl2-methyl-4-((trimethylsilyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate(compound 453.1 and compound 454.2, 4.00 g, 12.5 mmol, 1.00 equiv, 89%combined purity) in tetrahydrofuran (250 mL). The mixture was cooled to0-5° C. and N-bromosuccinimide (4.97 g, 27.9 mmol, 2.2 equiv) was addedto the reaction mixture in portions. The resulting mixture was stirredat 25° C. for 2 h, then concentrated in vacuo. The residue was purifiedby silica gel chromatography with ethyl acetate/petroleum ether(1:100-1:10) as the eluent to obtain a mixture of the title compounds asa yellow oil (2.50, 69%).

Compound 453.3 and compound 454.5.5-(5-(tert-Butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (453.3) and5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (454.5)

Into a 50-mL sealed tube, was placed a solution of a mixture oftert-Butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate and tert-butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 453.2 andcompound 454.4, 1.60 g, 5.48 mmol, 1.00 equiv) in N,N-dimethylformamide(10 mL). 5-Formyl-2,4-dimethylbenzoic acid (compound 16.3, 978 mg, 5.49mmol, 1.00 equiv), ammonium acetate (1.90 g, 24.7 mmol, 4.50 equiv), andammonium hydroxide (2.88 g, 16.4 mmol, 3.00 equiv, 20%) were added andthe resulting mixture was stirred for 2 h at 130° C. The mixture wascooled to 10-15° C. then quenched with ice water (50 mL). The resultingsolution was extracted with ethyl acetate (2×50 mL) and the organicswere combined. The pH of the aqueous was adjusted to 6 with hydrogenchloride (2 M) and extracted with ethyl acetate (2×150 mL) and allorganic extracts were combined, dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:4-2:1) as theeluent to obtain a mixture of the title compounds as a light yellow oil(480 mg, 23%).

Compound 453.4 and compound 454.6. tert-Butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453.4) and tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 454.6)

Into around-bottom flask, was placed a solution of a mixture of5-(5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid and5-(5-(tert-butoxycarbonyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoicacid (compound 453.3 and compound 454.5, 480 mg, 1.25 mmol, 1.00 equiv)in N,N-dimethylformamide (10 mL). DIEA (643 mg, 4.98 mmol, 4.00 equiv),EDC (476 mg, 2.48 mmol, 2.00 equiv), and 1-hydroxybenzotrizole (337 mg,2.50 mmol, 2.00 equiv) were added and the resulting solution was stirredat 25° C. for 20 min. 4-(Piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 276 mg, 1.24 mmol, 1.00 equiv) was then added in portionsat 0° C. The resulting solution was stirred at 25° C. for 16 h, and thenquenched with of ice water (40 mL). The resulting solids were collectedby filtration, and then dissolved in ethyl acetate (100 mL). Theresulting organics was washed with brine (2×30 mL), dried (Na₂SO₄),filtered and concentrated in vacuo to obtain a mixture of the titlecompounds as a light yellow oil (440 mg, 64%).

Compound 453.5 and compound 454.7.4-(1-(2,4-Dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 453.5) and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 454.7)

Into around-bottom flask, was placed a solution of a mixture oftert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-e]pyridine-5(4H)-carboxylateand tert-butyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-e]pyridine-5(4H)-carboxylate(compound 453.4 and compound 454.6, 440 mg, 0.790 mmol, 1.00 equiv) indichloromethane (10 mL) and trifluoroacetic acid (3 mL). The resultingsolution was stirred at 25° C. for 20 h, then concentrated in vacuo toobtain a mixture of the title compounds as a yellow oil (450 mg, 99%).

Compounds 453 and 454. Methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 453) and methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 454)

Into an 8-mL sealed tube, was placed a mixture of4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitrile2,2,2-trifluoroacetate (compound 453.5 and compound 454.7, 100 mg, 0.176mmol, 1.00 equiv) in dichloromethane (6 mL). DIEA (114 mg, 0.880 mmol,5.00 equiv) was added and the mixture was cooled to 0° C. Dimethyldicarbonate (29.6 mg, 0.220 mmol, 1.25 equiv) was added drop-wise withstirring at 0° C., and then the resulting solution was stirred for 2.5 hat 0-5° C. The resulting mixture was concentrated in vacuo and theresidue was purified by prep-HPLC (1#-Pre-HPLC-001(SHIMADZU)): Column,Xbridge Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH₃H₂Oand CH₃CN (39.0% CH₃CN up to 52.0% in 7 min, up to 100.0% in 1 min, downto 39.0% in 1 min); Detector, Waters 2489 254 & 220 nm. The titlecompounds were obtained from the prep-HPLC as a mixture of isomers (30mg). The isomeric mixture was purified by chiral-prep-HPLC (2#-Gilson Gx281(HPLC-09)): Column, Chiralpak IA, 2*25 cm, 5 um; mobile phase, Hex(0.1% DEA) and ethanol (0.2% TEA) (hold 50.0% ethanol (0.2% TEA) in 10min); Detector, UV 220/254 nm. The chiral-prep-HPLC fractions containingpure, separated products were appropriately combined and lyophilized toobtain methyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-6-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate (compound 453) as a white solid (14.2 mg, 13%) andmethyl2-(5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-4-methyl-6,7-dihydro-3H-imidazo[4,5-c]pyridine-5(4H)-carboxylate(compound 454) as white solid (11.8 mg, 10%). Compound 453: m/z (ES+)512 (M+H)⁺. Compound 454: m/z (ES+) 512 (M+H)⁺.

Compounds 455 & 456.4-(1-(5-(5,6-Dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 455) and4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 456)

Into a 10-mL sealed tube, was placed a solution of a mixture of4-(1-(2,4-dimethyl-5-(6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitriletrifluoroacetate and4-(1-(2,4-dimethyl-5-(4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)benzoyl)piperidin-4-yl)benzonitriletrifluoroacetate (compound 453.5 and compound 454.7, (100 mg, 0.22 mmol,1.00 equiv) in tetrahydrofuran (5 mL). Formaldehyde (1 mL, 37 wt %) andsodium triacetoxyborohydride (162 mg, 0.760 mmol, 3.5 equiv) were addedto the mixture and stirred for 2.5 h at 40° C. The mixture wasconcentrated in vacuo and the residue was purified by Prep-HPLC with thefollowing conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge PrepC18, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN(32% CH3CN up to 42% in 8 min, up to 100% in 2 min, down to 32% in 1min); Detector, Waters 2489 254 nm & 220 nm. The title compounds wereobtained from the prep-HPLC as a mixture of isomers (50 mg). Theisomeric mixture was purified by chiral-prep-HPLC with the followingconditions (2#-Gilson Gx 281(HPLC-09)): Column, Chiralpak IC, 2*25 cm, 5um; mobile phase, Hex(0.2% TEA) and ethanol(0.2% TEA) (hold 50.0%ethanol(0.2% TEA) in 27 min); Detector, UV 220/254 nm. Thechiral-prep-HPLC fractions containing pure, separated products wereappropriately combined and lyophilized to obtain4-(1-(5-(5,6-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 455) as a white solid (13.5 mg, 13%) and4-(1-(5-(4,5-dimethyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 456) as a white solid (6.8 mg, 7%). Compound 455: m/z (ES+)468 (M+H)⁺. Compound 456: m/z (ES+) 468 (M+H)⁺.

Compound 457.1 and compound 457.2. tert-Butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 457.1) andtert-butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound457.2)

Into a 1-L four neck round-bottom flask, which was purged and maintainedwith an inert atmosphere of nitrogen, was placed a solution oftert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (5.00 g, 23.4 mmol,1.00 equiv) in ether (700 mL). Ammonium acetate (904 mg, 11.7 mmol, 0.50equiv) and azobisisobutyronitrile (AIBN) (192 mg, 1.17 mmol, 0.05 equiv)were added. The mixture was cooled to 0° C., then N-bromosuccinimide(4.15 g, 23.5 mmol, 1.00 equiv) was added in portions. The resultingmixture was stirred for 4 h at 25° C., then concentrated in vacuo. Theresidue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:100-1:10) as the eluent to obtain a mixtureof the title compounds as a light yellow oil (4.10 g, 60%).

Compound 457.4-(1-(5-(5-Acetyl-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 400and compound 2, except a mixture of tert-butyl3-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound 457.1) andtert-butyl 5-bromo-2-methyl-4-oxopiperidine-1-carboxylate (compound457.2) was used in place of 3-bromo-5-methyldihydro-2H-pyran-4(3H)-one(compound 400.2). The product contains about 10% of the other methylregioisomer4-(1-(5-(5-acetyl-6-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile.m/z (ES+) 496 (M+H)⁺.

Compound 458.4-(1-(5-(5′-Acetyl-3′,4′,5′,6′-tetrahydrospiro[cyclopropane-1,7′-imidazo[4,5-c]pyridin]-2′-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 449and compound 2, except tert-butyl8-oxo-5-azaspiro[2.5]octane-5-carboxylate (Remen, L. et al. Bioorg. andMed. Chem. Lett., 2009, 32, 351-357) was used in place of3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+) 508(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.71 (d, J=8.1 Hz, 2H), 7.47 (d,J=7.8 Hz, 2H), 7.37-7.20 (m, 2H), 4.77 and 4.71 (2 singlets, acetylamide rotamers, CH₂, 2H), 3.77 and 3.72 ((2 singlets, acetyl amiderotamers, CH₂, 2H), 3.71-3.67 (m, 1H), 3.30-3.18 (m, 1H), 2.99 (t,J=11.6 Hz, 2H), 2.48-2.27 (m, 6H), 2.24 and 2.21 (2 singlets, acetylamide rotamers, acetyl CH₃, 3H), 2.10-1.95 (m, 1H), 1.92-1.52 (m, 3H),1.18-0.96 (m, 4H).

Compound 459.4-(1-(5-(6-Methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound449, except 4-methoxycyclohexanone (Kaiho, T. et al. J. Med. Chem.,1989, 32, 351-357) was used in place of3,3-dimethyldihydro-2H-pyran-4(3H)-one (compound 449.1). m/z (ES+) 469(M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.69 (d, J=8.1 Hz, 2H), 7.53-7.44 (m,2H), 7.37-7.21 (m, 2H), one proton estimated under methanol (1H),3.84-3.75 (m, 1H), 3.73-3.57 (m, 1H), 3.45 (s, 3H), 3.27-3.19 (m, 1H),3.05-2.91 (m, 3H), 2.79-2.58 (m, 3H), 2.46 (s, 3H), 2.40 and 2.29 (2singlets, amide rotamers, 3H), 2.17-1.92 (m, 3H), 1.92-1.67 (m, 3H).

Compound 460.4-(1-(5-(6-Hydroxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, was placed a solution of4-(1-(5-(6-methoxy-4,5,6,7-tetrahydro-1H-benzo[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile(compound 459, 80 mg, 0.17 mmol, 1.0 equiv) in a solvent mixture ofacetonitrile and dichloromethane (10/10 mL). Tetrachlorosilane (32 mg,0.19 mmol, 1.1 equiv) and sodium iodide (28 mg, 0.19 mmol, 1.1 equiv)were added to the reaction and the resulting mixture was stirredovernight at 20° C. The reaction was quenched with aqueous sodiumbicarbonate (10 mL) and the aqueous was extracted with ethyl acetate(3×10 mL). The combined organics was dried (Na₂SO₄), filtered andconcentrated in vacuo and the residue was purified by silica gelchromatography with ethyl acetate as the eluent to obtain the titlecompound as a yellow solid (7.1 mg, 9%). m/z (ES+) 455 (M+H)⁺.

Compound 461.1. 4-Methoxyhepta-1,6-diene

Into a round-bottom flask, was placed a solution of hepta-1,6-dien-4-ol(2.00 g, 17.8 mmol, 1.00 equiv) and iodomethane (5.00 g, 35.2 mmol, 2.00equiv) in tetrahydrofuran (30 mL). The solution was cooled to 0° C. andsodium hydride (1.00 g, 25.0 mmol, 1.50 equiv, 60% in mineral oil) wasadded to the reaction in portions. The resulting mixture was stirredovernight at room temperature, then carefully quenched with water (5 mL)and diluted with of ether (30 mL). The organics was washed with brine(2×20 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to obtainthe title compound as a colorless oil (2.00 g, 84%).

Compound 461.2. 4-Methoxycyclopent-1-ene

Into around-bottom flask, which was purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-methoxyhepta-1,6-diene (compound 461.1, 200 mg, 1.43 mmol, 1.00 equiv,90%) in dichloromethane (25 mL). Grubbs II catalyst (55 mg, 0.06 mmol,0.04 equiv) was added and the resulting solution was stirred overnightat room temperature. The mixture was concentrated in vacuo to obtain thetitle compound as a colorless oil (100 mg, 57%).

Compound 461.3. 2-Bromo-4-methoxycyclopentanol

Into a round-bottom flask, was added a solution of4-methoxycyclopent-1-ene (compound 461.2, 1.00 g, 8.66 mmol, 1.00 equiv,85%) in dichloromethane (100 mL) and a solution of N-bromosuccinimide(2.00 g, 11.3 mmol, 1.00 equiv) in water (20 mL). The reaction mixturewas stirred at room temperature for 3 hours and then the resultingmixture was washed with water (20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to obtain the title compound as a colorless oil(1.00 g, 36%).

Compound 461.4. 2-Bromo-4-methoxycyclopentanone

Into a round-bottom flask, was placed a solution of2-Bromo-4-methoxycyclopentanol (compound 461.3, 1.00 g, 3.08 mmol, 1.00equiv, 60%) in dichloromethane (100 mL). Dess-Martin periodinane (2.00g, 4.72 mmol, 1.10 equiv) was added in portions and the mixture wasstirred overnight at room temperature. The mixture was then diluted withwater (20 mL) and quenched with Na₂S₂O₄ (4 g). The aqueous was extractedwith dichloromethane (100 mL) and the combined organics was washed withbrine (30 mL), dried (Na₂SO₄), filtered and concentrated in vacuo toobtain the title compound as a brown oil (800 mg, 81%).

Compound 461.5. Methyl5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate

Into around-bottom flask, was placed a solution of2-bromo-4-methoxycyclopentanone (compound 461.4, 600 mg, 1.86 mmol, 60%)in ACN (15 mL). Methyl 5-carbamimidoyl-2,4-dimethylbenzoatehydrochloride (compound 2.5, 320 mg) and potassium carbonate (430 mg,3.11 mmol) were added and the mixture was stirred overnight at 80° C.The mixture was concentrated in vacuo and the residue was diluted withethyl acetate (50 mL) and then washed with brine (2×20 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography with dichloromethane/methanol (10:1) as theeluent to obtain the title compound as a brown oil (200 mg, 27%).

Compound 461.6. Methyl5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate

Into around-bottom flask, was placed a solution of methyl5-(3a-hydroxy-5-methoxy-1,3a,4,5,6,6a-hexahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 461.5, 200 mg, 0.38 mmol, 1.00 equiv, 60%) inN,N-dimethylformamide (mL). p-Toluenesulfonic acid (20 mg, 0.12 mmol,0.18 equiv) was added and the resulting solution was stiffed overnightat 80° C., then concentrated in vacuo. The residue was purified bysilica gel chromatography with dichloromethane/methanol (10:1) as theeluent to obtain the title compound as a brown oil (100 mg, 66%).

Compound 461.7.5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoicacid

Into around-bottom flask, was placed a solution of methyl5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate(compound 461.6, 100 mg, 0.270 mmol, 1.00 equiv, 80%) in methanol (3mL). A solution of sodium hydroxide (67.0 mg, 1.68 mmol, 5.00 equiv) inwater (3 mL) was added and the resulting mixture was stirred overnightat 70° C., then concentrated in vacuo. The residue was diluted withwater (3 mL) and the pH of the solution was adjusted to 2-3 with aqueoushydrogen chloride (12 M). The mixture was extracted ethyl acetate (3×10mL), and the combined organics was concentrated in vacuo to obtain thetitle compound as a brown solid (80 mg, 84%).

Compound 461.4-(1-(5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, was placed a solution of5-(5-Methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoicacid (compound 461.7, 60 mg, 0.17 mmol, 1.00 equiv, 80%) inN,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 46 mg, 0.20 mmol, 1.00 equiv),4-dimethylaminopyridine (52 mg, 0.43 mmol, 2.00 equiv), and EDC.HCl (80mg, 0.42 mmol, 2.00 equiv) were added and the mixture was stiffedovernight at room temperature. The resulting solution was diluted withethyl acetate (30 mL) and washed with brine (3×10 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The residue (40 mg) was purified bypreparative-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um;mobile phase, water with 0.05% TFA and CH₃CN (15.0% CH₃CN up to 55.0% in7 min, up to 100.0% in 1 min, down to 15.0% in 1 min); Detector, Waters2489 254 & 220 nm. The fractions containing pure product were combinedand lyophilized to obtain the title compound as a white solid (8.9 mg,11%). m/z (ES+) 455 (M+H)⁺.

Compound 462.1. 5-Bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one

Into around-bottom flask, was placed a solution of2,2-dimethyloxan-4-one (1.00 g, 7.80 mmol, 1.00 equiv) in ether (20 mL).N-Bromosuccinimide (1.50 g, 25.5 mmol, 3.26 equiv) was added inportions, followed by the addition of ammonium acetate (60.0 mg, 0.78mmol, 0.10 equiv). The resulting mixture was stirred overnight at 25°C., then diluted with ethyl acetate (20 mL). The resulting mixture waswashed brine (2×40 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:30) as the eluent to obtain the titlecompound as a yellow oil (508 mg, 31%).

Compound 462.4-(1-(5-(6,6-Dimethyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)-2,4-dimethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except 5-bromo-2,2-dimethyldihydro-2H-pyran-4(3H)-one (compound462.1) was used in place of 2-bromo-4-methoxycyclopentanone (compound461.4). m/z (ES+) 469 (M+H)⁺.

Compound 463.1. Trimethyl((4-(trimethylsilyl)but-3-yn-1-yl)oxy)silane

Into a 1-L three neck round-bottom flask, was placed a solution ofbut-3-yn-1-ol (20.0 g, 285 mmol, 1.00 equiv) in tetrahydrofuran (300 mL)and the mixture was purged with nitrogen. The mixture was cooled to −78°C., then n-butyllithium (2.5 M in THF) (270 mL, 2.40 equiv) was addeddrop-wise followed by the addition of chlorotrimethylsilane (67.9 g, 625mmol, 2.20 equiv). The resulting mixture was then stirred for 1 h at 25°C., then carefully quenched with aqueous sodium bicarbonate (250 mL).The aqueous was extracted with ether (3×100 mL) and the combinedorganics was dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography with ether/petroleumether (1:10-1:1) as the eluent to obtain the title compound as acolorless oil (10.0 g, 16%).

Compound 463.2. Trimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane

Into a round-bottom flask, was placed a solution of compound 463.1, 2.00g, 7.46 mmol, 1.00 equiv, 80%) in hexane (30 mL). The system was purgedwith nitrogen. Quinoline (0.1 mL, 0.10 equiv) and Lindlar reagent(poisoned by Pb) (0.2 g, 0.10 equiv, 5%) were added to the mixture. Theresulting mixture was hydrogenated overnight at room temperature underatmosphere pressure of hydrogen. After completion of the reaction, thesystem was purged with nitrogen and the solids were removed byfiltration. The filtrate was concentrated in vacuo and the residue waspurified by silica gel chromatography with hexane/ether (20:1) as theeluent to obtain the title compound as a colorless oil (1.50 g, 74%).

Compound 463.3. 6-Methyl-3,6-dihydro-2H-pyran

Into around-bottom flask, was placed a mixture oftrimethyl((4-(trimethylsilyl)but-3-en-1-yl)oxy)silane (compound 463.2,1.50 g, 6.93 mmol, 1.00 equiv), acetaldehyde (900 mg, 20.4 mmol, 3.00equiv), and indium(III) chloride (1.50 g, 1.00 equiv) in dichloromethane(15 mL). The resulting mixture was stirred overnight at 25° C., thendiluted with DCM (50 mL). The organics was washed with brine (3×20 mL),dried (Na₂SO₄), filtered and concentrated in vacuo to obtain the titlecompound as a brown oil (0.600 g, 88%).

Compound 463.4 and compound 463.5.4-Bromo-2-methyldihydro-2H-pyran-3(4H)-one (compound 463.4) and3-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 463.5)

Into a round-bottom flask, was placed a solution of o-iodoxybenzoic acid(IBX) (3.42 g, 6.11 mmol, 2.00 equiv) in DMSO (12 mL). The mixture wasstiffed for 30 min at 25° C. then a solution of6-methyl-3,6-dihydro-2H-pyran (compound 463.3, 600 mg, 4.28 mmol, 1.00equiv, 70%) in dichloromethane (30 mL) was added drop-wise. The mixturewas cooled to 0-5° C., then N-bromosuccinimide (1.20 g, 6.74 mmol, 1.10equiv) was added portion-wise. The resulting mixture was stiffedovernight at 25° C., then the solids were removed by filtration. Thefiltrate was diluted with dichloromethane (50 mL) and washed with brine(3×20 mL). The mixture was dried (Na₂SO₄), filtered and concentrated invacuo. The residue was purified by silica gel chromatography with ethylacetate/petroleum ether (1:20) as the eluent to obtain a mixture of thetitle compounds as a brown oil (600 mg, 73%).

Compound 463.4-(1-(2,4-Dimethyl-5-(4-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except a mixture of 4-bromo-2-methyldihydro-2H-pyran-3(4H)-one(compound 463.4) and 3-bromo-2-methyldihydro-2H-pyran-4(3H)-one(compound 463.5) was used in place of 2-bromo-4-methoxycyclopentanone(compound 461.4). m/z (ES+) 455 (M+H)⁺.

Compound 464.1. 4-(Allyloxy)pent-1-ene

A 500-mL four neck round-bottom flask was purged and maintained with aninert atmosphere of nitrogen, then a suspension of sodium hydride (14.0g, 350 mmol, 2.01 equiv, 60%) in N,N-dimethylformamide (100 mL) wasadded. The mixture was cooled to 0° C., then a solution ofpent-4-en-2-ol (15.0 g, 174 mmol, 1.00 equiv) in N,N-dimethylformamide(100 mL) was added drop-wise and the mixture was stirred for 20 min at0° C. The mixture was cooled to −20° C. and a solution of3-bromoprop-1-ene (20.9 g, 172 mmol, 0.99 equiv) inN,N-dimethylformamide (100 mL) was added. The resulting mixture wasallowed to warm to room temperature and stirred overnight, thencarefully quenched with H₂O (500 mL). The aqueous was extracted withethyl acetate (4×100 mL) and the combined organics was washed with brine(2×200 mL), dried (Na₂SO₄), filtered and concentrated in vacuo to obtainthe title compound as a yellow oil (13.3 g, 61%).

Compound 464.2. 2-Methyl-3,6-dihydro-2H-pyran

A 500-mL three neck round-bottom flask was purged and maintained with aninert atmosphere of nitrogen, then a solution of 4-(allyloxy)pent-1-ene(compound 464.1, 3.00 g, 23.8 mmol, 1.00 equiv) in DCE (200 mL) wasadded. Grubbs catalyst was added (810 mg, 0.950 mmol, 0.04 equiv) andthe mixture was stirred at 60° C. for 4 h. The mixture was thenconcentrated in vacuo at 20° C. to obtain the title compound as acolorless oil (2.00 g, 86%).

Compound 464.3 and 464.4. 4-Bromo-6-methyltetrahydro-2H-pyran-3-ol and5-bromo-2-methyltetrahydro-2H-pyran-4-ol

Into a round-bottom flask, was placed a solution ofmethyl-3,6-dihydro-2H-pyran (compound 464.2, 2.00 g, 20.4 mmol, 1.00equiv) in a mixture of tetrahydrofuran and H₂O (20/20 mL).N-Bromosuccinimide (3.60 g, 20.3 mmol, 1.00 equiv) was added and theresulting mixture was stiffed at room temperature overnight. The mixturewas extracted with dichloromethane (2×20 mL) and the combined organicswere washed with brine (2×20 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo to obtain a mixture of the title compounds as ayellow oil (1.10 g, crude).

Compound 464.5 and 464.6. 4-Bromo-6-methyldihydro-2H-pyran-3(4H)-one and5-bromo-2-methyldihydro-2H-pyran-4(3H)-one

Into around-bottom flask, was placed a mixture of4-bromo-6-methyltetrahydro-2H-pyran-3-ol (compound 464.3) and5-bromo-2-methyltetrahydro-2H-pyran-4-ol (compound 464.4) (1.10 g, 5.64mmol, 1.00 equiv) as a solution in dichloromethane (30 mL). Dess-Martinperiodinane (2.90 g, 6.84 mmol, 1.21 equiv) was added and the resultingsolution was stirred overnight at room temperature, then quenched withwater (20 mL). The aqueous was extracted with dichloromethane (2×20 mL)and the combined organics were washed with brine (2×50 mL), dried(Na₂SO₄), filtered and concentrated in vacuo to obtain a mixture of thetitle compounds as a yellow oil (0.7 g).

Compound 464.7. Methyl2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate

Into around-bottom flask, was placed a mixture of4-bromo-6-methyldihydro-2H-pyran-3(4H)-one (compound 464.5) and5-bromo-2-methyldihydro-2H-pyran-4(3H)-one (compound 464.6) (700 mg,3.63 mmol) as a solution in acetonitrile (20 mL). Methyl5-carbamimidoyl-2,4-dimethylbenzoate hydrochloride (compound 2.5, 750mg) and potassium carbonate (1.00 g, 7.25 mmol) were added and themixture was stirred overnight at 75° C. under nitrogen. The mixture wascooled and the solids were removed by filtration. The filtrate wasconcentrated in vacuo and the residue was purified by silica gelchromatography with ethyl acetate/petroleum ether (1:1) as the eluent toobtain the title compound as a yellow solid (100 mg, 9%).

Compound 464.8.2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoicacid

Into around-bottom flask, was placed a solution of methyl2,4-dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoate(compound 464.7, 100 mg, 0.330 mmol, 1.00 equiv) in methanol (10 mL). Asolution of lithium hydroxide (76 mg, 3.17 mmol, 10.0 equiv) in water(10 mL) was added and the resulting solution was stiffed for 4 h at roomtemperature. The mixture was concentrated in vacuo and then aqueous HClwas added until the pH was 5-6. The mixture was adjusted to pH 5-6 withaqueous HCl and then the resulting mixture was concentrated in vacuo.MeOH (5 mL) was added to the residue and the solids were removed byfiltration. The filtrate was concentrated in vacuo to obtain the titlecompound as a yellow solid (60 mg, 63%).

Compound 464.4-(1-(2,4-Dimethyl-5-(6-methyl-3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, was placed a solution of2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoicacid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL).EDC.HCl (67 mg, 0.35 mmol, 2.00 equiv), 4-dimethylaminopyridine (64 mg,0.52 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride(compound 1.5, 39 mg, 0.18 mmol, 1.00 equiv) were added and the solutionwas stiffed for 2 h at room temperature. The reaction was quenched withwater (20 mL) and the aqueous was extracted with ethyl acetate (2×20mL). The combined organics was dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by silica gel chromatography withethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20mg) was purified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep Phenyl, 5 um, 19*150mm; mobile phase, water with 0.03% NH₃H₂O and CH₃CN (30% CH₃CN up to 60%in 9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters2489 254 nm & 220 nm. The fractions containing pure product werecombined and lyophilized to obtain the title compound as a white solid(8.0 mg, 10%). m/z (ES+) 455 (M+H)⁺.

Compound 465.2-(5-(4-(4-Cyanophenyl)piperidine-1-carbonyl)-2,4-dimethylphenyl)-1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carbonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound461, except cyclopent-3-enecarbonitrile (Johnson, C. R. et al. J. Org.Chem., 1969, 34, 860-864) was used in place of 4-methoxycyclopent-1-ene(compound 461.2). m/z (ES+) 450 (M+H)⁺.

Compound 466.1. Tetrahydrofuran-3,4-diyl dimethanesulfonate

Into a round-bottom flask, was placed a solution oftetrahydrofuran-3,4-diol (500 mg, 4.80 mmol, 1.00 equiv) andtriethylamine (1.45 g, 14.3 mmol, 3.00 equiv) in dichloromethane (8 mL).The mixture was cooled to 0-5° C. and a solution of methanesulfonylchloride (1.40 g, 12.2 mmol, 2.50 equiv) in dichloromethane (2 mL) wasadded drop-wise. The solution was stirred at room temperature for 2 h,and then diluted with dichloromethane (100 mL). The solution was washedwith aqueous NH₄Cl (2×30 mL) then brine (30 mL), dried (Na₂SO₄),filtered and concentrated in vacuum to obtain the title compound as abrown solid (1.00 g, 72%).

Compound 466.2. 3,4-Diazidotetrahydrofuran

Into a round-bottom flask, was placed a mixture oftetrahydrofuran-3,4-diyl dimethanesulfonate (compound 466.1, 2.00 g,7.30 mmol, 1.00 equiv, 95%) and sodium azide (4.00 g, 61.5 mmol, 8.00equiv) in N,N-dimethylformamide (20 mL). The resulting mixture wasstirred overnight at 100° C. behind a blast shield, then cooled anddiluted with ether (100 mL). The mixture was washed with brine (5×20mL), dried (Na₂SO₄), filtered and concentrated in vacuo to obtain thetitle compound as a colorless oil (1.00 g, 80%).

Compound 466.3. Tetrahydrofuran-3,4-diamine

Into around-bottom flask, was placed a solution of3,4-diazidotetrahydrofuran (compound 466.2, 900 mg, 5.26 mmol, 1.00equiv, 90%) in ethanol (10 mL). The system was purged with nitrogen andpalladium on carbon (10 wt % Pd) (900 mg) was added. After furtherpurging the system with nitrogen, the atmosphere was changed to hydrogenand the resulting suspension was stirred overnight at room temperatureunder an atmosphere of hydrogen. After purging the system with nitrogen,the solids were removed by filtration and the filtrate was concentratedin vacuo to obtain the title compound as a colorless oil (600 mg, 98%).

Compound 466.4. Methyl 5-(imino(methoxy)methyl)-2,4-dimethylbenzoatehydrochloride

Into a 50-mL three neck round-bottom flask, was placed a solution ofmethyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900 mg, 4.28 mmol,1.00 equiv, 90%) in methanol (20 mL). Hydrogen chloride gas wasintroduced by bubbling through the solution for 0.5 hr. The reactionmixture was then transferred into a 30-mL sealed tube and stirredovernight at room temperature. The mixture was concentrated under vacuumand the residue was diluted with ethyl acetate (30 mL) and extractedwith water (10 mL). The aqueous was concentrated in vacuo to obtain thetitle compound as a white solid (200 mg, 15%).

Compound 466.5. Methyl2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate

Into around-bottom flask, was placed a solution oftetrahydrofuran-3,4-diamine (compound 466.3, 140 mg, 1.17 mmol, 1.00equiv, 85%) in ethanol (6 mL). Methyl5-(imino(methoxy)methyl)-2,4-dimethylbenzoate hydrochloride (compound466.4, 300 mg, 0.930 mmol, 1.00 equiv) and triethylamine (140 mg, 1.38mmol, 1.00 equiv) were added and the resulting solution was stirredovernight at 80° C., then concentrated in vacuo. The residue waspurified by silica gel chromatography with dichloromethane/methanol(10:1) as the eluent to obtain the title compound as a brown oil (120mg, 34%).

Compound 466.5.2,4-Dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoicacid

Into around-bottom flask, was placed a solution of methyl2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoate(compound 466.5, 100 mg, 0.330 mmol, 1.00 equiv, 90%) and sodiumhydroxide (73 mg, 1.82 mmol, 5.00 equiv) in methanol/H₂O (3/3 mL). Theresulting solution was stirred overnight at 70° C., then concentrated invacuum. The residue was diluted with H₂O (5 mL) and the pH of thesolution was adjusted to 2-3 with hydrogen chloride (12 N), thenextracted with ethyl acetate (3×10 mL). The combined organics wasconcentrated in vacuo to obtain the title compound as a yellow solid(80.0 mg, 84%).

Compound 466.4-(1-(2,4-Dimethyl-5-(-3a,4,6,6a-tetrahydro-1H-furo[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

Into around-bottom flask, was placed a solution of2,4-dimethyl-5-(3a,4,6,6a-tetrahydro-1H-furo[3,4-c]imidazol-2-yl)benzoicacid (compound 466.5, 80.0 mg, 0.250 mmol, 1.00 equiv, 80%) inN,N-dimethylformamide (4 mL). 4-(Piperidin-4-yl)benzonitrilehydrochloride (compound 1.5, 82.0 mg, 0.350 mmol, 1.20 equiv),4-dimethylaminopyridine (76.0 mg, 0.620 mmol, 2.00 equiv), and EDC.HCl(116 mg, 0.610 mmol, 2.00 equiv) were added and the resulting solutionwas stiffed overnight at room temperature. The mixture was diluted withethyl acetate (30 mL) and washed with brine (3×15 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product (50 mg) waspurified by Prep-HPLC with the following conditions(1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep C18, 5 um, 19*150 mm;mobile phase, water with 0.05% TFA and CH₃CN (15% CH₃CN up to 50% in 9min, up to 100% in 1 min, down to 15% in 1 min); Detector, Waters 2489254 nm & 220 nm. The fractions containing pure product were combined andlyophilized to obtain the title compound as a white solid (13 mg, 12%).m/z (ES+) 429 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.70 (d, 2H), 7.53-7.36(m, 4H), 5.09 (s, 2H), 4.17 (d, J=10.8 Hz, 2H), 3.77 (d, J=10.5 Hz, 2H),3.60-3.44 (m, 1H), ˜3.3 (m, partially overlapped with water, 1H),3.10-2.92 (m, 2H), 2.48 (s, 3H), 2.45 and 2.35 (2 singlets, amiderotamers, Ar—CH₃, 3H), 2.10-1.97 (m, 1H), 1.92-1.52 (m, 3H).

Compound 467.4-(1-(4-Fluoro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1and compound 2, except 4-fluoro-2-methylbenzoic acid was used in placeof 2,4 dimethylbenzoic acid. m/z (ES+) 445 (M+H)⁺.

Compound 468.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-methylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except 4-chloro-2-methylbenzoic acid was used in place of 2,4dimethylbenzoic acid. m/z (ES+) 502 (M+H)⁺.

Compound 469.1-(2-(2-Chloro-5-(4-(4-fluorophenyl)piperidine-1-carbonyl)-4-methylphenyl)-6,7-dihydro-3H-imidazo[4,5-c]pyridin-5(4H)-yl)ethanone

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2and compound 468. m/z (ES+) 495 (M+H)⁺.

Compound 470.1. Methyl 2-bromo-4-fluorobenzoate

Into a round-bottom flask, was placed a solution of2-bromo-4-fluorobenzoic acid (21.8 g, 99.5 mmol, 1.00 equiv) in asolvent mixture of sulfuric acid (20 mL) and methanol (20 mL). Theresulting solution was stirred for 5 h at 85° C., then cooled and cooledand concentrated in vacuo. The residue was diluted with ethyl acetate(200 mL) and washed with brine (200 mL) then aqueous NaHCO₃ (100 mL.Note: gas evolution), dried (Na₂SO₄), filtered and concentrated in vacuoto obtain the title compound as a light yellow oil (22.0 g, 95%).

Compound 470.1. Methyl 2-ethyl-4-fluorobenzoate

The title compound (colorless oil, 14.5 g, 93%) was prepared using aprocedure similar to that used for the preparation of compound 48.1 andusing of methyl 2-bromo-4-fluorobenzoate (compound 470.1, 20.0 g) inplace of methyl 2-bromo-4-methylbenzoate.

Compound 470.4-(1-(2-Ethyl-4-fluoro-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 1and compound 2, except methyl 2-ethyl-4-fluorobenzoate (compound 470.1)was used in place of 2,4-dimethylbenzoic acid, and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 477 (M+H)⁺.

Compound 471.1. 4-Chloro-5-iodo-2-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound2.1, except 4-chloro-2-methylbenzoic acid was used in place of2,4-dimethylbenzoic acid.

Compound 471.2. 4-Chloro-5-formyl-2-methylbenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound392.2, except 4-chloro-5-iodo-2-methylbenzoic acid (compound 471.1) wasused in place of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound392.1).

Compound 471.4-(1-(4-Chloro-2-methyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound400, except 4-chloro-5-formyl-2-methylbenzoic acid (compound 471.2) wasused in place of 2-ethyl-5-formyl-4-methylbenzoic acid (compound 211.4),3-bromodihydro-2H-pyran-4(3H)-one was used in place of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 479 (M+H)⁺.

Compound 472.1. Methyl 4-chloro-2-ethyl-5-iodobenzoate

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound211.2, except methyl 4-chloro-2-ethylbenzoate (compound 178.2) was usedin place of methyl 2-ethyl-4-methylbenzoate (compound 48.1).

Compound 472.2. 4-Chloro-2-ethyl-5-iodobenzoic acid

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound211.3, except methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1)was used in place of 2-ethyl-5-iodo-4-methylbenzoate (compound 211.2).

Compound 472.4-(1-(4-Chloro-2-ethyl-5-(3,4,6,7-tetrahydropyrano[3,4-d]imidazol-2-yl)benzoyl)-4-fluoropiperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound400, except 4-chloro-2-ethyl-5-iodobenzoic acid (compound 472.2) wasused in place of 2-ethyl-5-formyl-4-methylbenzoic acid (211.4),3-bromodihydro-2H-pyran-4(3H)-one was used in place of3-bromo-5-methyldihydro-2H-pyran-4(3H)-one (compound 400.2) and4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2) wasused in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound1.5). m/z (ES+) 493 (M+H)⁺.

Compound 473.4-(1-(5-(5-Acetyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-chloro-2-ethylbenzoyl)piperidin-4-yl)benzonitrile

The title compound was prepared using standard chemical manipulationsand procedures similar to those used for the preparation of compound 2,except methyl 4-chloro-2-ethyl-5-iodobenzoate (compound 472.1) was usedin place of methyl 5-iodo-2,4-dimethylbenzoate (compound 2.2). m/z (ES+)516 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δ 7.73-7.54 (m, 4H), 7.53-7.42 (m,2H), 4.75 and 4.70 (2 singlets, acetyl amide rotamers, CH₂, 2H),4.02-3.88 (m, 2H), 3.68-3.52 (m, 1H), 3.32-3.20 (m, 1H), 3.07-2.88 (m,3H), 2.88-2.58 (m, 3H), 2.25 and 2.22 (2 singlets, acetyl amiderotamers, acetyl CH₃, 3H), 2.11-1.98 (m, 1H), 1.93-1.53 (m, 3H),1.39-1.22 (m, 3H).

Additional example compounds are found in Table 1.

Example 1 FASN Inhibition by Compounds of the Present Disclosure

Determination of FASN Biochemical Activity

The FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breastcancer cell-line with high levels of FASN expression. It is estimatedthat FASN comprises about 25% of the cytosolic proteins in this cellline. SKBr3 cells were homogenized in a dounce homogenizer thencentrifuged for 15 minutes at 4° C. to remove particulate matter. Thesupernatant was then analyzed for protein content, diluted to theappropriate concentration, and used to measure FASN activity. Thepresence of FASN was confirmed by western blot analysis. A similarmethod for isolation of FASN from SKBr3 cells is described in Teresa, P.et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

FASN activity of the SKBr3 cell extract was determined by measuringeither NADPH oxidation or the amount of thiol-containing coenzyme A(CoA) released during the fatty acid synthase reaction. The dye CPM(7-diethylamino-3-(4′-maleimidyl-phenyl)-4-methylcoumarin) contains athiol reactive group that increases its fluorescence emission onreaction with the sulfhydryl group of CoA. The biochemical activitiesshown in Table 1 were determined using the fluorescence measurement ofCoA release via a procedure described in Chung C. C. et al. (Assay andDrug Development Technologies, 2008, 6(3), 361-374).

Example 2 Antiviral Activity

The antiviral activity of Structure (I-Z) was assessed using the HCV1breplicon system:

The replicon was constructed using the ET (luc-ubi-neo/ET) cell line, aHuh7 human hepatoma cell line harboring an HCV replicon with a stableluciferase (Luc) reporter and three cell culture-adaptive mutations(Pietschmann, et al (2002) J. Virol. 76:4008-4021). The HCV repliconantiviral evaluation assay examined the effects of compounds at sixhalf-log concentrations. Human interferon alpha-2b was included in eachrun as a positive control compound. Sub-confluent cultures of the ETline were plated out into 96-well plates that are dedicated for theanalysis of cell numbers (cytotoxicity) or antiviral activity and thenext day drugs were added to the appropriate wells. Cells were processed72 hr later when the cells were still sub-confluent. EC₅₀(concentrations inhibiting the replicon by 50% and 90%, respectively),IC₅₀ (concentration decreasing cell viability by 50%) and SI (selectiveindex: IC₅₀/EC₅₀) values were determined HCV RNA replicon levels wereassessed as either HCV RNA replicon-derived Luc activity or as HCV RNAby TaqMan RT-PCR. Two methods were used to estimate cell counts(cytotoxicity). When the Luc assay system was employed, the colorimetricCytoTox-1 cell proliferation assay (Promega) was used to estimate cellnumbers, while while ribosomal RNA (rRNA) levels determined via TaqManRT-PCR were used as an indication of cell numbers in the RNA-basedassay. A summary of the results is listed below in Table 2.

TABLE 2 Replicon EC50 Cell IC50 Method (μM) (μM) Selectivity IndexLuciferase activity 0.017 >32 >1882 TaqMan RT-PCR 0.105 >100 >952

Example 3 FASN Inhibition Correlates to HCV Inhibition

The antiviral activities of 15 compounds of the present disclosure(numbers correlate to the compounds in Table 1) were measured using theHCV replicon system. Replicon cell line 1b (HCV 1b/Luc-Neo replicon (1bCon1 with Firefly gene integrated)) was established following publishedmethods (Lohmann et al. (1999) Science 285(5424):110-113, Lohmann et al.(2001) J. Virol. 75(3):1437-1449 and Qi et al. (2009) Antiviral Res.81(2):166-173) using Huh7 by G418 selection. The replicon was assembledusing synthetic gene fragments. The GT1b line has PV-EKT and harbors 3adaptive mutations E1202G(NS3), T1280I(NS3), K1846T(NS4B) and thebackbone is Con1. The culture medium was:

-   -   a) DMEM supplement with 10% FBS, G418 (250 μg/ml), streptomycin        (100 μg/ml)/penicillin (100 U/ml), L-glutamine (100×), NEAA        (100×)    -   b) Media prepared as follows:        -   i) 500 ml DMEM media (Gibco, Cat#11960-077)        -   ii) 57 ml Fetal Bovine Serum (Gibco, Cat#16140-071)        -   iii) 5.7 ml Penicillin-Streptomycin (Gibco, Cat#15140-122)        -   iv) 5.7 ml MEM non-essential amino acids (Gibco,            Cat#111140-050)        -   v) 5.7 ml L-glutamine (Gibco, Cat#125030-081)        -   vi) 574.1 ml media+2.87 ml 50 mg/ml G418 [final 0.25 mg/m1]            (Gibco, Cat#10131-027)

Compounds were dissolved in DMSO to provide a 10 mM stock or used fromstock DMSO solutions. Compounds were diluted to generate 10-point halflog (3.16-fold) serial dilutions for assay in 384-well plates (Echoqualified 384-well PP (Labcyte Cat#P-05525)) plus DMSO in duplicate.This experiment was repeated three times on three different days.

Cells were harvested when confluency reached 90%-100%. Cellconcentrations were adjusted to 8×10⁴ cells/ml and added to 384-wellwhite assay microplates (tissue-culture treated—Greiner Cat#781080) toreach a final cell density of 2,000 cells/well. Plates were incubated at5% CO₂ and 37° C. for 72 hours.

After 72 hours of incubation Bright-Glo Luciferase reagent (Promega,cat#E2650) and Cell Titer Flo (Promega, cat#G6080/1/2) were prepared andstored in the dark while equilibrating to room temperature. Treatedcells were likewise equilibrated to room temperature. 10 μL of CellTiter Flo was added to each well of compound-treated cells and incubatedin microtiter plates for approx. 0.5 hours. Cell viability was measuredusing an Envision reader (available from Perkin Elmer) to estimatecytotoxicity. 30 μL of firefly luciferase substrate were added to eachwell and chemiluminescence was measured as an indicator of the extent ofHCV replication.

The anti-replicon activity (% inhibition) is calculated using theequation:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \frac{{Cmpd} - {Control}}{{DMSO} - {Control}}} \right) \times 100.}$Cytotoxicity  is  calculated  using  the  equation:${\% \mspace{14mu} {Cytotoxicity}} = {\left( {1 - \frac{{Cmpd} - {Background}}{{DMSO} - {Background}}} \right) \times 100.}$

There was determined to be a correlation between potency of FASNinhibition and antiviral activity as illustrated in Table 3 below andFIG. 1. It is noted that none of the compounds caused significantcytotoxicity.

TABLE 3 Molecule Biochemical IC50 (μM) Antiviral EC50 (μM) 1 0.230 0.4252 0.065 0.192 12 0.370 1.003 14 0.263 0.260 20 0.022 0.011 27 0.1070.153 43 0.110 0.154 55 0.035 0.034 58 0.025 0.078 67 0.090 0.270 680.100 0.301 70 0.037 0.099 73 0.040 0.117 152 0.052 0.072 343 0.6000.624

Example 4 FASN Inhibitors Retain Activity against HCV Mutants thatConfer Resistance to Direct-acting Antiviral Agents

One of the major challenges in treating hepatitis C is the rapidemergence of resistance in response to direct-acting antiviral agents.Resistance typically results when the virus generates a point mutantthat supports essential viral functions but prevents antiviral agentsfrom binding. Three FASN inhibitors (compounds 55, 20, and 70) weretested for their ability to inhibit mutants of HCV that conferresistance to representative antiviral agents. Each of these mutants wasintroduced into a GT1b construct based on a Con1 backbone containing thePVIRES-Luciferase Ubi-Neo gene and harboring 1 adaptive mutation(S2204I). (Lohmann et al. (1999) Science 285(5424):110-113, Lohmann etal. (2001) J. Virol. 75(3):1437-1449 and Qi et al. (2009) Antiviral Res.81(2):166-173). Antiviral activities were measured by the methoddescribed in Example 3.

The studied mutations are shown in Table 4 below.

TABLE 4 Studied Mutations Mutant Reference NS3 A156T Susser et al J.Clin. Virol. 52(4), 321-327 (2011) and references therein NS3 R155KSusser et al J. Clin. Virol. 52(4), 321-327 (2011) and referencestherein NS4B H94R Rai et al. Antiviral Res. 90, 93-101 (2011) NS5AY393HFridell et a.l Antimicrob. Agents Chemother. 54(9), 3641-3650 (2010)NS5B M423I (non-nucleoside site) Troke et al. Antimicrob. AgentsChemother. 56(3), 1331-1341 (2012) NS5B S282T (nucleoside site) Dutartreet al. Antimicrob. Agents Chemother. 50(12), 4161-4169 (2006)

A known NS4B allosteric inhibitor (Compound A), a known NS5A inhibitor(Compound B), a known non-nucleoside NS5B inhibitor (Compound C), aknown NS3/NS4A protease inhibitor (Compound D) and a known nucleosideNS5B inhibitor (Compound E) were tested in parallel with the FASNinhibitors of the present disclosure to confirm the performance of theresistance mutations.

Antiviral EC₅₀'s for the various compounds against the panel of mutants,along with the relative shift in EC₅₀ relative to the GT1b wild-typereplicon are shown below. Normal assay variation is ±3-4 fold. EC₅₀shifts outside this range imply resistance and are indicated in bold.The 3 FASN inhibitors retain activity across the panel of mutants,whereas the direct-acting antiviral agents display resistance againstmutations in their respective binding sites.

TABLE 5 Antiviral EC₅₀'s. EC₅₀ (nM) 1b Wild NS3 NS3 NS4B NS5A NS5B NS5BCompound Type A156T R155K H94R Y93H M423I S282T 55 49.63 143.00 156.1067.31 109.40 19.22 73.30 20 16.71 44.06 25.46 17.02 32.00 19.70 25.60 7039.18 49.97 43.91 36.00 108.90 58.69 56.90 Compound A 261.00 232.20209.60 2813.00 n.t. 126.60 n.t. Compound B 0.01 0.01 n.t. n.t. 0.28 0.010.01 Compound D 0.67 105.00 236.60 0.39 n.t. 1.54 n.t. Compound C 4.274.57 8.43 4.61 3.00 34.09 3.00 Compound E 583.70 890.90 n.t. n.t. 1069.0159.30 15650.0

TABLE 6 Fold shift in EC50 relative to wild-type HCV Fold shift in EC50relative to wild-type Binding NS3 NS3 NS4B NS5A NS5B NS5B Compound SiteA156T R155K H94R Y93H M423I S282T 55 2.88 3.15 1.36 2.20 0.39 1.48 202.64 1.52 1.02 1.92 1.18 1.53 70 1.28 1.12 0.92 2.78 1.50 1.45 CompoundA NS4B 0.89 0.80 10.78 n.t. 0.49 n.t. Compound B NS5A 1.00 n.t. n.t.35.13  0.75 0.88 Compound D NS3/4A 156.46 352.56 0.58 n.t. 2.29 n.t.Compound C NS5B 1.07 1.98 1.08 0.70 7.99 0.70 (non-nuc) Compound E NS5B1.53 n.t. n.t. 1.83 0.27 26.81  (nuc)

Example 5 FASN Inhibitors Useful in Combination Therapies

This example describes the in vitro antiviral activity and cytotoxicityof the compound of Structure (V-K) in combination with IFN-α, Ribavirin,Compounds B, C, D and E against an HCV GT1b replicon cell line.

Materials:

Virus:

The GT1b replicon plasmid was assembled using synthetic gene fragments.The replicon genome contains PVIRES-Luciferase Ubi-Neo gene segments andharbors 1 adaptive mutation (S22041), and the backbone is Con1. Thereplicon GT1b cell line was established by the following publishedmethods.

Medium and Reagents:

Table 7 below provides details regarding the culture medium reagentsused in this example.

TABLE 7 List of culture medium regents Reagent Vendor Catalogue NumberDimethyl sulfoxide (DMSO) Sigma Cat #34869-100ML DMEM Invitrogen Cat#11960-044 Fetal Bovine Serum (FBS) Gibco Cat #16140 Pen-StrepInvitrogen Cat #15140-122 MEM non-essential amino acids Invitrogen Cat#11140-050 L-Glutamin Invitrogen Cat #25030-081 G418 (geneticin) GibcoCat #10131-027 Trypsin/EDTA Invitrogen Cat #25200-072 DPBS/ModifiedHyclone SH30028.01B 96-well cell plate Greiner Cat #655090 Cell titerfluro Promega Cat #G6082 Bright-Glo Promega Cat #E264B

Analytical Instruments:

The following analytical instruments were used to perform the assays ofthis example:

-   -   POD-810    -   Topcount (PE)    -   Envision (PE)    -   Multidrop (Thermo)

Methods:

Preparation of Compound Plates for Single Compound Testing:

Compounds were supplied as dry powders and were reconstituted in DMSO togenerate stock solutions. The POD-810 system was used to generate10-point half log (3.16-fold) serial dilutions for the assay in 96-wellplates. The highest test concentrations are detailed for each compoundin Table 8.

Assay Protocol (Single Compounds):

Each compound was assayed with 3.16-fold (half log) serial dilutions for10 concentrations plus DMSO in duplicate. HCV replicon GT1b cells wereharvested and adjusted to a cell concentration of 8E+04 cells/ml. AMultidrop was used to plate 100 μL/well into 96 assay microplates toreach a final cell density of 8,000 cells/well. Plates were incubated at5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luiferase reagent and Cell TiterFlo were prepared and stored in dark while equilibrating to roomtemperature. The cell plates were allowed to equilibrate to roomtemperature as well. A Multidrop was used to add 20 μL Cell Titer Flo toeach well of compound-treated and compound-free cells. The plates areincubated for 1 hour, and cell viability is measured on an Envisionreader for cytoxicity calculation. Fifty microliters of fireflyluciferase substrate are added to each well, incubated for 2 minutes,and chemi-luminescence is measured for EC₅₀ calculation.

The anti-replicon activity (% inhibition) was calculated using thefollowing equation:

% Inhibition=[1−((Compound−background)/(DMSO−background))×100].

Test Compounds and Assay Setup for Two-Compound Combination Studies:

The DMSO stocks of the compounds used in the single compound testingwere also used in this analysis. Combination dilution matrixes weregenerated by POD-810 in 96-well assay microplates. The POD-810 systemwas used to generate 7-point, 2-fold serial dilutions in a matrixformat. The maximum concentration tested for each compound is detailedbelow.

TABLE 8 Expected activities and upper concentrations of compounds testedin single-agent and combination studies Highest concentra- Highestconcentra- Expected tion for single- tion for combina- GT1b EC50 agenttesting tion testing Compound (μM) (μM) (μM) (V—K) 0.060 10.0 0.100Compound D 0.0014 0.032 0.0032 Compound C 0.018 10.0 0.032 Compound B0.000009 0.001 0.000032 Compound E 4.030 100.0 10.0 IFN 64.94 IU/ml 1000IU/ml 10.0 IU/ml Ribavirin 26.830 320.0 100.0

The compound of Structure (V-K) was tested alone and in combination withcompounds detailed in Table 9. Each compound was also tested alone as asingle agent.

TABLE 9 Combinations of compounds for in vitro evaluation. RegimenCombination 1 (V—K) + Compound D 2 (V—K) + Compound C 3 (V—K) + CompoundB 5 (V—K) + Compound E 6 (V—K) + IFN-α 7 (V—K) + RBV

Assay Setup (Two-Drug Combinations):

Each compound was assayed with 2-fold serial dilutions for 7concentrations in matrix format plus each drug alone. HCV replicon GT1bcells were harvested and adjusted to a cell concentration of 8E+04cells/ml. A Multidrop was used to plate 100 μL into 96 assay microplatesto reach a final cell density of 8,000 cells/well. Plates were incubatedat 5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luiferase reagent and Cell TiterFlo were prepared and store in dark while allowing to equilibrate toroom temperature. The cells plates were allowed to equilibrate to roomtemperature as well. A Multidrop was used to add 20 μL Cell Titer Flo toeach well of compound-treated and compound-free cells. The plates wereincubated for 1 hour, and cell viability was measured on an Envisionreader for cytotoxicity calculation. The liquid was then removed fromthe plates, after which 50 μl PBS and 50 μl firefly luciferase substratesolution were added to each well, after a 2-minute incubation period,chemiluminescence (for HCV replication calculation) was measured. Thedata were analyzed using MacSynergy™ II.

Assay Results:

Activity and Cytotoxicity of the Compounds.

The EC₅₀ and CC₅₀ values are summarized below in Table 10.

TABLE 10 EC₅₀ and CC₅₀ of Each Test Compound GT1b Expected EC₅₀ CompoundEC₅₀ (μM) (μM) CC₅₀ (μM) (V—K) 0.04 0.06 >10 Compound D 0.00210.0014 >0.032 Compound C 0.006 0.018 >10 Compound B 0.0000120.000009 >0.001 Compound E 2.41 4.03 >100 IFN-α (IU/mL) 1.34 1 >1000 RBV32.75 26.83 239

Combination Effect.

The combination effect of the compound pairs was calculated usingMacSynergy™ II and those results are summarized in Table 11 below.

TABLE 11 Summary of the combination effects of the compound pairsMacSynergy ™ II SYNERGY PLOT (95%) Compd 1 Compd 2 Log ANTAG- Log (topconc) (top conc) SYNERGY volume ONISM volume (V—K) Compound D 16.7 1.51−13.03 −1.18 Compound C 2.93 0.27 −9.2 −0.83 Compound B 6.75 0.61 −7.11−0.64 Compound E 1.08 0.1 −7.81 −0.73 IFN-α 5.44 0.49 −24.88 −2.25 RBV1.64 0.15 −3.52 −0.32 * None of the combinations cause cytotoxicity.

CONCLUSIONS

The Z factors of the compound pairs summarized in Table 12 indicate thatthe assay quality is better than the QC standard.

TABLE 12 Summary of the Z factor of compound pairs Z factor Drug PairsPlate-1 Plate-2 Plate-3 (V—K) + Compound D 0.68 0.86 0.83 (V—K) +Compound C 0.66 0.78 0.65 (V—K) + Compound B 0.70 0.83 0.84 (V—K) +Compound E 0.72 0.76 0.74 (V—K) + IFN-α 0.75 0.70 0.66 (V—K) + RBV 0.780.78 0.72

The EC₅₀ values of the individual compounds in the combination matrix(summarized in Table 13) are consistent with the EC₅₀ data in obtainedfor single-compound inhibition Table 10.

TABLE 13 Summary of EC₅₀ of single dose in compound combination GT1bEC₅₀ (μM) in EC₅₀ (μM) of single dose ranging dose in drug Compoundassay combination (V—K) 0.04 0.07 Compound D 0.0021 0.0017 Compound C0.006 0.009 Compound B 0.000012 0.000009 Compound E 2.41 1.79IFN-α(IU/mL) 1.34 3.43 RBV 32.75 31.63

The compound of Structure (V-K) was demonstrated to have additiveantiviral activity without enhanced cytotoxicity in combination withagents representing a variety of mechanisms. These results aresummarized in Table 14 below.

TABLE 14 Summary of antiviral mechanisms that are additive with thecompound of Structure (V—K). Molecule Mechanism Class IFN-α Cellulardefense Host RBV Multiple Host Compound D HCV Protease DAA Compound BNS5A Inhibitor DAA Compound C NS5B Inhibitor DAA Compound E NS5BInhibitor DAA The term “direct-acting antiviral” (“DAA”) refers to acompound that binds to and inhibits a viral protein, rather than a hostprotein.

IFN-α and RBV represent current standard-of-care for treating HepatitisC infection, and the HCV protease inhibitors Telaprevir and Boceprivirhave recently been approved. The additive antiviral activity and lack ofenhanced cytotoxicity in combination with IFN-α and RBV further suggestthat compounds of this invention will not interfere with critical hostprocesses such as cellular defense (IFN-α) or guanidine nucleotidebiosynthesis (RBV). Compounds of this invention such as the compound ofStructure (V-K) should therefore be therapeutically useful ifadministered in combination regimens with current standard of care.Moreover, the additive antiviral activities observed with Compound B,Compound C, and Compound E suggest that molecules of this invention suchas the compound of Structure (V-K) can be productively combined withagents currently in development that target newer mechanisms (e.g., NS5Aand NS5B inhibitors).

Example 6 Anti-Tumor Activity—Multiplexed Cytotoxicity Assay

Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-Glutamine, 1 mMNa pyruvate or a special medium in a humidified atmosphere of 5% CO₂ at37° C. Cells were seeded into 384-well plates and incubated in ahumidified atmosphere of 5% CO₂ at 37° C. Compounds were added 24 hourspost cell seeding. At the same time, a time zero untreated cell platewas generated.

After a 72 hour incubation period, cells were fixed and stained withfluorescently labeled antibodies and nuclear dye to allow visualizationof nuclei, apoptotic cells and mitotic cells. Apoptotic cells weredetected using an anti-active caspase-3 antibody. Mitotic cells weredetected using an anti phospho-histone-3 antibody.

Compounds were serially diluted in half-log (3.16-fold) increments andassayed over 10 concentrations in a final assay concentration of 0.1%DMSO from the highest test concentration specified in the sampleinformation chapter. Automated fluorescence microscopy was carried outusing a GE Healthcare IN Cell Analyzer 1000, and images were collectedwith a 4× objective.

Twelve bit tiff images were acquired using the InCell Analyzer 1000 3.2and analyzed with Developer Toolbox 1.6 software. EC₅₀ and IC₅₀ valueswere calculated using nonlinear regression to fit data to a sigmoidal 4point, 4 parameter One-Site dose response model, where: y(fit)=A+[(B−A)/(1+((C/x)̂D))]. Curve-fitting, EC₅₀/IC₅₀ calculations andreport generation are performed using a custom data reduction engineMathIQ based software (AIM).

The multiplexed cytotoxicity assay uses a cell image based analysistechnique where cells are fixed and stained with fluorescently labeledantibodies and nuclear dye to visualize nuclei, and apoptotic andmitotic cells. Apoptotic cells are detected using an anti-activecaspase-3 antibody. Mitotic cells are detected using an antiphospho-histone-3 antibody.

Cell proliferation is measured by the signal intensity of theincorporated nuclear dye. The cell proliferation assay output isreferred to as the relative cell count. To determine the cellproliferation end point, the cell proliferation data output istransformed to percent of control (POC) using the following formula:

POC=relative cell count (compound wells)/relative cell count (vehiclewells)×100

Time zero non-treated plate is used to determine number of doublings in72 hour assay period: Number of doublings in 72 hours=LN[Cell number (72hrs end point)*Cell number (time zero)]/LN(2). The output of eachbiomarker is fold increase over vehicle background normalized to therelative cell count in each well.

The activated caspase-3 marker labels cells from early to late stageapoptosis. The output is shown as a fold increase of apoptotic cellsover vehicle background normalized to the relative cell count in eachwell. Concentrations of test compound that cause a 5-fold induction inthe caspase-3 signal indicates significant apoptosis induction. Wellswith concentrations higher than the relative cell count IC₉₅ areeliminated from the caspase3 induction analysis.

The phospho-histone-3 marker labels mitotic cells. The output is shownas a fold induction of mitotic cells over vehicle background normalizedto the relative cell count in each well. When the fold induction ofmitotic cell signal over background is ˜1, there is “no effect” on thecell cycle. Two or more fold increase in phospho-histone-3 signal overvehicle background indicates significant test compound induction ofmitotic block.

Two or more fold decrease in the phospho-histone-3 signal may indicateG1/S block only when cytotoxicity levels are below the measured relativecell count IC₉₅. When 2 or more fold decrease in the phospho-histone-3signal are observed at concentrations higher than the relative cellcount IC₉₅, the decrease in mitotic cell counts are most likely due to amore general cytotoxicity effect rather than a true G1/S phase block.Wells with concentrations higher than the relative cell count IC₉₅ areeliminated from the phospho-histone-3 analysis.

Cell proliferation measured by relative cell counts were the criteriafor positive response.

Apoptosis:

-   -   >5-fold increase in activated caspase-3 signal indicates an        apoptotic response

Mitosis:

-   -   >2-fold increase in phospho-histone-3 indicates mitotic block    -   <2-fold decrease in phospho-histone-3 indicates G1/S block

TABLE 15 Results G1/S cell Max G2/M Biochemical cycle block cell cycleMax Apoptosis Compound IC₅₀ (μM) (μM) block Fold Induction 205 0.2200.160 1.36 2.39 95 0.030 0.012 0.94 2.45 142 0.140 0.031 1.28 2.34 1530.060 0.014 1.17 2.55 427 0.080 0.019 1.00 2.39 42 0.070 0.013 1.09 2.2048 0.170 0.027 1.27 2.20 156 0.030 0.031 1.28 2.59 182 0.150 0.030 1.542.07 183 0.170 0.031 1.00 2.40

While preferred aspects of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch aspects are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the invention. It should be understood thatvarious alternatives to the aspects of the invention described hereincan be employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

ID Structure FASN IC50 (μM) 1

0.230 2

0.065 2.9

0.60 3

0.146 4

0.200 5

0.055 6

0.360 7

0.050 8

0.125 9

0.040 11

0.170 12

0.370 13

0.260 14

0.263 15

0.180 16

0.058 17

0.073 18

0.990 19

0.870 20

0.022 21

0.045 22

0.085 23

0.070 24

0.070 25

0.150 26

7.195 27

0.107 28

0.490 29

0.980 30

0.320 31

0.060 32

0.215 33

7.500 34

0.080 35

25.083 36

0.130 37

0.675 38

2.345 39

1.710 40

0.050 41

0.035 42

0.067 43

0.110 44

0.180 45

0.147 46

0.050 47

0.230 48

0.170 49

0.040 50

0.520 51

1.700 52

31.650 53

1.970 54

0.310 55

0.035 56

2.800 57

0.030 58

0.025 60

0.045 61

0.230 62

0.093 63

0.510 64

0.170 65

0.090 66

0.230 67

0.090 68

0.100 69

0.065 70

0.037 71

0.030 72

0.200 73

0.040 74

0.120 75

0.130 76

0.035 77

0.080 78

0.035 79

0.045 80

0.400 81

0.200 82

0.077 83

0.090 84

5.320 85

1.450 86

5.420 87

0.310 88

0.040 89

0.030 90

0.380 91

2.210 92

0.940 93

0.550 94

5.260 95

0.030 96

0.030 97

0.025 98

0.900 99

0.220 100

>50 101

>50 102

0.085 103

0.035 104

0.130 105

0.015 106

0.900 107

1.490 108

1.050 109

0.250 110

0.280 111

0.135 112

1.295 113

0.130 114

0.245 115

0.480 116

0.090 117

0.090 118

0.350 119

120

0.460 121

2.300 122

0.890 123

0.690 124

32.880 125

>50 126

>50 127

0.730 128

2.260 129

>50 130

0.300 131

0.220 132

0.450 133

0.790 134

1.330 135

2.040 136

0.240 137

0.500 138

0.640 139

1.210 140

0.380 141

>50 142

0.175 143

0.140 144

0.320 145

0.820 146

0.260 147

0.250 148

0.180 149

0.240 150

0.300 151

0.420 152

0.052 153

0.055 154

0.105 155

0.020 156

0.030 157

0.090 158

0.057 159

0.070 160

0.055 161

0.040 162

0.115 163

0.135 164

>50 165

1.000 166

0.160 167

0.125 168

0.060 169

0.090 170

0.090 171

0.070 172

0.140 173

0.240 174

0.200 175

0.310 176

5.990 177

2.110 178

0.555 179

1.260 180

8.230 181

0.115 182

0.145 183

0.170 184

0.085 185

0.080 186

0.055 187

0.065 188

0.070 189

0.270 190

5.060 191

0.200 192

0.300 193

0.440 194

0.400 195

>50 196

>50 197

11.105 198

0.705 199

1.060 200

13.520 201

23.140 202

0.055 203

0.045 204

0.195 205

0.220 206

0.320 207

0.300 208

0.100 209

0.105 210

0.310 211

0.830 212

7.190 213

0.790 214

28.760 215

0.080 216

0.090 217

0.100 218

0.170 219

0.085 220

0.055 221

0.250 222

0.065 223

0.030 224

0.160 225

0.140 226

0.055 227

0.070 228

0.110 229

0.090 230

30.990 231

0.300 232

0.650 233

1.630 234

>50 235

0.030 236

0.060 237

0.080 238

0.100 239

0.050 240

0.050 241

0.120 242

0.050 243

0.120 244

0.220 245

0.020 246

0.050 247

0.020 248

0.060 249

0.070 250

0.030 251

0.580 252

0.180 253

0.090 254

0.090 255

0.410 256

0.090 257

0.580 258

0.150 259

1.330 260

3.500 261

21.750 262

5.343 263

0.250 264

>50 265

>50 266

>50 267

30.260 268

0.390 269

1.350 270

1.980 271

0.520 272

0.300 273

0.060 274

2.345 275

2.245 276

9.060 277

11.680 278

1.750 279

0.330 280

0.700 281

42.300 282

30.090 283

1.000 284

1.005 285

>50 286

>50 287

>50 288

289

32.733 290

0.470 291

0.370 292

0.270 293

1.080 294

295

3.820 296

3.250 297

0.025 298

299

300

301

302

>50 303

304

0.680 305

>50 306

2.900 307

5.360 308

2.750 309

310

8.780 311

312

0.025 313

1.630 314

0.047 315

0.267 316

0.690 317

1.170 318

0.037 319

0.195 320

1.020 321

0.030 322

0.180 323

0.360 324

1.175 325

0.340 326

2.750 327

0.610 328

0.220 329

8.870 330

0.120 331

0.085 332

0.050 333

334

0.140 335

0.490 336

0.420 337

0.165 338

0.035 339

0.093 340

0.080 341

0.085 342

0.090 343

0.600 344

0.250 345

0.140 346

0.330 347

0.300 348

0.455 349

>50 350

32.600 351

>50 352

0.880 353

18.500 354

0.380 355

0.140 356

>50 357

0.230 358

0.805 359

0.105 360

0.280 361

0.360 362

0.247 363

0.050 364

37.000 365

0.310 366

1.100 367

368

0.310 369

7.150 370

371

372

373

>50 374

3.580 375

6.360 376

6.070 377

2.550 378

379

0.705 380

0.420 381

>50 382

>50 383

>50 384

>50 385

8.867 386

387

>50 388

13.380 389

16.600 390

>50 391

>50 392

0.025 393

0.065 394

0.135 395

0.260 396

0.050 397

0.040 398

0.035 399

0.030 400

0.260 401

0.065 402

0.077 403

0.045 404

0.040 405

0.010 406

0.020 407

0.040 408

0.145 409

0.020 410

0.010 411

0.035 412

0.035 413

0.065 414

0.033 415

0.040 416

0.055 417

0.020 418

0.050 419

0.010 420

0.020 421

0.050 422

0.020 423

0.175 424

0.165 425

0.075 426

0.060 427

0.080 428

0.040 429

0.060 430

0.035 431

0.025 432

0.065 433

0.040 434

0.470 435

0.365 436

0.040 437

0.050 438

0.060 439

0.110 440

0.050 441

0.140 442

12.480 443

0.060 444

0.040 445

0.490 446

0.390 447

448

10.610 449

0.135 450

0.105 451

0.070 452

0.130 453

0.070 454

0.077 455

0.130 456

0.135 457

0.080 458

0.130 459

0.310 460

0.090 461

0.105 462

0.780 463

0.440 464

0.065 465

0.050 466

34.670 467

1.810 468

0.170 469

2.100 470

1.130 471

0.450 472

0.230 473

0.110 474

0.180 475

0.050 476

>50 477

0.130 478

0.420 479

0.110 480

0.180 481

21.240 482

0.240 483

0.100 484

0.070 485

0.130 486

0.540 487

0.380 488

0.030 489

0.180 490

0.090 491

0.070 492

0.030 493

0.090 494

>50

1. A compound of Structure (IX):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl.
 2. The compound ofclaim 1 wherein R²⁴ is C₁-C₄ straight or branched alkyl or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein t is 0 or
 1. 3.The compound of claim 1 wherein R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom.
 4. The compound ofclaim 1 wherein R³ is H or halogen.
 5. The compound of claim 1 whereinR¹ is halogen, —CN or C₁-C₂ haloalkyl.
 6. The compound of claim 1wherein both L¹ and L² are N.
 7. The compound of claim 1 wherein R²¹ isC₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl.
 8. The compoundof claim 1 wherein R²¹ is C₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl. 9.The compound of claim 1 wherein R²⁴ is —(C₁-C₂ alkyl)_(t)-O—(C₁-C₂alkyl) wherein t is 0 or
 1. 10. The compound of claim 1 wherein R²¹ isC₃-C₅ cycloalkyl, R²² is C₁-C₂ alkyl and R²⁴ is C₁-C₂ alkyl.
 11. Thecompound of claim 10 wherein R²¹ is cyclobutyl, R²² is C₁-C₂ alkyl andR²⁴ is C₁-C₂ alkyl.
 12. The compound of claim 1 wherein R²¹ iscyclobutyl.
 13. The compound of claim 1 wherein R³ is H or F.
 14. Thecompound of claim 1 wherein R¹ is —CN.
 15. The compound of claim 1wherein R¹ is —CF₃.
 16. The compound of claim 1 wherein R²² is H, methylor ethyl.
 17. The compound of claim 16 wherein R²² is H.
 18. Thecompound of claim 1 wherein R²² is methyl.
 19. The compound of claim 1wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl,R²² is methyl, L¹ and L² are N, and R²⁴ is methyl, ethyl, hydroxymethyl,methoxymethyl, 2-methoxyethyl.
 20. The compound of claim 1 wherein R¹ is—CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl,L¹ and L² are N, and R²⁴ is methoxy or ethoxy.
 21. The compound of claim1 wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ is methyl, ethyl,hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
 22. The compound ofclaim 1 wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ is methyl, ethyl,hydroxymethyl, methoxymethyl, or 2-methoxyethyl.
 23. The compound ofclaim 1 having a formula selected from the group consisting of:


24. A compound of Structure (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R⁶⁰)₂, O or NR⁵⁰;each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O_(t)—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹.
 25. The compound ofclaim 24 wherein R²¹ is halogen, C₁-C₄ straight or branched alkyl orC₃-C₅ cycloalkyl.
 26. The compound of claim 24 wherein R³ is H orhalogen.
 27. The compound of claim 24 wherein R¹ is —CN or C₁-C₂haloalkyl.
 28. The compound of claim 24 wherein R³ is H or F.
 29. Thecompound of claim 24 wherein R¹ is —CN.
 30. The compound of claim 24wherein R¹ is —CF₃.
 31. The compound of claim 24 wherein n is
 1. 32. Thecompound of claim 24 wherein n is
 2. 33. The compound of claim 24wherein m is
 1. 34. The compound of claim 24 wherein m is
 2. 35. Thecompound of claim 24 wherein R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyl andR²² is C₁-C₂ alkyl.
 36. The compound of claim 24 wherein R²¹ is C₃-C₅cycloalkyl and R²² is C₁-C₂ alkyl.
 37. The compound of claim 24 whereinn is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂ alkyl).
 38. The compound of claim24 wherein L³ is NR⁵⁰; R⁵⁰ is C₁-C₂ alkyl; R²¹ is cyclobutyl; R²² is Hor methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or
 2. 39. The compoundof claim 24 wherein n is 2, m is 1, L³ is O and s is
 0. 40. The compoundof claim 24 wherein R²² is H, methyl or ethyl.
 41. The compound of claim24 wherein R²² is methyl.
 42. The compound of claim 24 wherein R²² is H.43. The compound of claim 24 wherein R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ whereinR⁵⁰ is methyl or ethyl.
 44. The compound of claim 24 wherein R¹ is —CN,each R² is H, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is2 and L³ is O.
 45. The compound of claim 24 having a formula selectedfrom the group consisting of:


46. A compound having Structure (VI-J):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl.
 47. The compound of claim 46 wherein R³ is H or halogen. 48.The compound of claim 46 wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.49. The compound of claim 46 wherein R²² is C₁-C₂ alkyl.
 50. Thecompound of claim 46 wherein R²¹ is cyclobutyl and R²² is C₁-C₂ alkyl.51. The compound of claim 46 wherein R²¹ is cyclobutyl.
 52. The compoundof claim 46 wherein R³ is H or F.
 53. The compound of claim 46 whereinR¹ is —CN.
 54. The compound of claim 46 wherein R¹ is —CF₃.
 55. Thecompound of claim 46 wherein R²² is H, methyl or ethyl.
 56. The compoundof claim 46 wherein R²² is H.
 57. The compound of claim 46 wherein R²²is methyl.
 58. The compound of claim 46 wherein R³⁵ is —C(O)—NHR³⁵¹. 59.The compound of claim 58 wherein R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
 60. Thecompound of claim 59 wherein R³⁵¹ is (R)-(tetrahydrofuran-2-yl)methyl or(S)-(tetrahydrofuran-2-yl)methyl.
 61. The compound of claim 46 whereinR¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² isH, R³⁵ is —C(O)—NHR³⁵¹ where R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
 62. Thecompound of claim 61 wherein R³⁵ is —C(O)—O—R³⁵¹.
 63. The compound ofclaim 62 wherein R³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.
 64. The compound of claim 63 wherein R³⁵¹is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.
 65. The compoundof claim 46 wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ is isopropyl,isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.
 66. Thecompound of claim 46 having a formula selected from the group consistingof:


67. A compound having Structure (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).
 68. The compound of claim 67wherein R³ is H or halogen.
 69. The compound of claim 67 wherein R¹ ishalogen, —CN, or C₁-C₂ haloalkyl.
 70. The compound of claim 67 whereinR²¹ is C₃-C₄ cycloalkyl and R²² is C₁-C₂ alkyl.
 71. The compound ofclaim 67 wherein R²¹ is cyclobutyl and R²² is C₁-C₂ alkyl.
 72. Thecompound of claim 67 wherein R²¹ is cyclobutyl.
 73. The compound ofclaim 67 wherein R³ is H or F.
 74. The compound of claim 67 wherein R¹is —CN.
 75. The compound of claim 67 wherein R¹ is —CF₃.
 76. Thecompound of claim 67 wherein R²² is H, methyl or ethyl.
 77. The compoundof claim 67 wherein R²² is H.
 78. The compound of claim 67 wherein R²²is methyl.
 79. The compound of claim 71 wherein R¹ is —CN, each R² is H,R³ is H or F, R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl orethyl.
 80. The compound of claim 71 having a formula selected from thegroup consisting of:


81. A pharmaceutical composition comprising the compound of claim 1 anda pharmaceutically acceptable carrier, excipient, or diluent.
 82. Apharmaceutical composition comprising the compound of claim 24 and apharmaceutically acceptable carrier, excipient, or diluent.
 83. Apharmaceutical composition comprising the compound of claim 46 and apharmaceutically acceptable carrier, excipient, or diluent.
 84. Apharmaceutical composition comprising the compound of claim 67 and apharmaceutically acceptable carrier, excipient, or diluent.
 85. A methodof treating viral infection in a subject comprising administering to thesubject a therapeutically effective amount of the compound of claim 1.86. The method of claim 85 wherein the viral infection compriseshepatitis C infection.
 87. A method of treating viral infection in asubject comprising administering to the subject a therapeuticallyeffective amount of the compound of claim
 24. 88. The method of claim 87wherein the viral infection comprises hepatitis C infection.
 89. Amethod of treating viral infection in a subject comprising administeringto the subject a therapeutically effective amount of the compound ofclaim
 46. 90. The method of claim 89 wherein the viral infectioncomprises hepatitis C infection.
 91. A method of treating viralinfection in a subject comprising administering to the subject atherapeutically effective amount of the compound of claim
 67. 92. Themethod of claim 91 wherein the viral infection comprises hepatitis Cinfection.
 93. A method of treating a condition characterized bydisregulation of a fatty acid synthase function in a subject byadministering to the subject a therapeutically effective amount of thecompound of claim
 1. 94. A method of treating a condition characterizedby disregulation of a fatty acid synthase function in a subject byadministering to the subject a therapeutically effective amount of thecompound of claim
 24. 95. A method of treating a condition characterizedby disregulation of a fatty acid synthase function in a subject byadministering to the subject a therapeutically effective amount of thecompound of claim
 46. 96. A method of treating a condition characterizedby disregulation of a fatty acid synthase function in a subject byadministering to the subject a therapeutically effective amount of thecompound of claim
 67. 97. A method of treating cancer in a subjectcomprising administering to the subject a therapeutically effectiveamount of amount of the compound of claim
 1. 98. The method of claim 97wherein the cancer is breast cancer.
 99. A method of treating cancer ina subject comprising administering to the subject a therapeuticallyeffective amount of amount of the compound of claim
 24. 100. The methodof claim 99 wherein the cancer is breast cancer.
 101. A method oftreating cancer in a subject comprising administering to the subject atherapeutically effective amount of amount of the compound of claim 46.102. The method of claim 101 wherein the cancer is breast cancer.
 103. Amethod of treating cancer in a subject comprising administering to thesubject a therapeutically effective amount of amount of the compound ofclaim
 67. 104. The method of claim 103 wherein the cancer is breastcancer.